5, 6-D2 uridine nucleoside/tide derivatives

ABSTRACT

In one aspect, the invention provides compounds represented by Formula I, 
                         
and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, and combinations thereof, pharmaceutical compositions comprising these compounds and the use of these compounds for treating a viral infection in a subject.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/759,555, filed on Feb. 1, 2013. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceuticalcompositions useful as antiviral and antiproliferative agents.Specifically, the present invention relates to 5,6-d₂ uridinenucleoside/tide derivatives and methods for their preparation and use.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughoutthe world. In the US, an estimated 4.5 million Americans are chronicallyinfected with HCV. Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the US in 1997. Worldwide over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver diseases and 30% of allliver transplants. Chronic HCV infection accounts for 30% of allcirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDCestimates that the number of deaths due to HCV will minimally increaseto 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989)Science 244:359-362), HCV is now widely accepted as the most commoncausative agent of post-transfusion non-A, non-B hepatitis (NANBH) (Kuo,G et al (1989) Science 244:362-364). Due to its genome structure andsequence homology, this virus was assigned as a new genus in theFlaviviridae family. Like the other members of the Flaviviridae, such asflaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) andpestiviruses (e.g. bovine viral diarrhea virus, border disease virus,and classic swine fever virus) (Choo, Q-L et al (1989) Science244:359-362; Miller, R. H. and R. H. Purcell (1990) Proc. Natl. Acad.Sci. USA 87:2057-2061), HCV is an enveloped virus containing a singlestrand RNA molecule of positive polarity. The HCV genome isapproximately 9.6 kilobases (kb) with a long, highly conserved,noncapped 5′ nontranslated region (NTR) of approximately 340 bases whichfunctions as an internal ribosome entry site (IRES) (Wang C Y et al.)‘An RNA pseudoknot is an essential structural element of the internalribosome entry site located within the hepatitis C virus 5′ noncodingregion’ RNA—A Publication of the RNA Society. 1(5): 526-537, 1995 July).This element is followed by a region which encodes a single long openreading frame (ORF) encoding a polypeptide of ˜3000 amino acidscomprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directlytranslated into a polypeptide of ˜3000 amino acids comprising both thestructural and nonstructural viral proteins. This large polypeptide issubsequently processed into the individual structural and nonstructuralproteins by a combination of host and virally-encoded proteinases (Rice,C. M. (1996) in B. N. Fields, D. M. Knipe and P. M. Howley (eds)Virology 2^(nd) Edition, p 931-960; Raven Press, N.Y.). There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are severalnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease. NS5A is a membrane-anchored phosphoprotein that isobserved in basally phosphorylated (56 kDa) and hyperphosphorylated (58kDa) forms. While its function has not fully been elucidated, NS5A isbelieved to be important in viral replication. The NS5B protein (591amino acids, 65 kDa) of HCV (Behrens, S. E. et at (1996) EMBO J. 1512-22), encodes an RNA-dependent RNA polymerase (RdRp) activity andcontains canonical motifs present in other RNA viral polymerases. TheNS5B protein is fairly well conserved both intra-typically (˜95-98%amino acid (aa) identity across 1b isolates) and inter-typically (˜85%aa identity between genotype 1a and 1b isolates). The essentiality ofthe HCV NS5B RdRp activity for the generation of infectious progenyvirions has been formally proven in chimpanzees (A. A. Kolykhalov etal., (2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition ofNS5B RdRp activity (inhibition of RNA replication) is predicted to beuseful to treat HCV infection.

Current standard of care (SOD) therapy is the combination ofpeg-interferon-a and ribavirin. However, this therapy is limited in itsclinical effectiveness and only ˜50% of genotype 1a patients respond tothe therapy. Recent approved NS3 protease inhibitors, Boceprevir andTelaprevir, used in combination with SOC slightly improvedeffectiveness, but suffered significant side effects, such as rash.Therefore, there is still significant unmet medical need for moreeffective agents.

Inhibitors of HCV NS5B as potential therapies for HCV infection havebeen reviewed: S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis CTherapeutics: Current Status and Emerging Strategies, Nature Rev. DrugDiscov. 1, 867-881 (2002). The potential for the emergence of resistantHCV strains and the need to identify compounds with Pan-genotypiccoverage supports the continuing efforts to identify novel and moreeffective nucleosides or nucleotides as HCV NS5B polymerase inhibitors.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds represented by FormulaI, or pharmaceutically acceptable salts, esters, stereoisomer, tautomer,solvate, or combination thereof:

wherein:

-   D is deuterium;-   R₁ is selected from the group consisting of:    -   1) Hydrogen;    -   2) R₆; where R₆ is selected from the group consisting of:        hydrogen, hydroxy protecting group, —C(O)R₇, —C(O)OR₇, and        —C(O)NR_(8a)R_(8b); wherein R₇ is selected from the group        consisting of: substituted or unsubstituted —C₁-C₈ alkyl,        substituted or unsubstituted —C₂-C₈ alkenyl, substituted or        unsubstituted —C₂-C₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, and substituted or        unsubstituted heterocyclic; R_(8a) and R_(8b) are each        independently selected from the group consisting of: hydrogen        and R₇; or alternatively R_(8a) and R_(8b) taken together with        the nitrogen atom to which they are attached form a heterocyclic        ring;    -   3) —P(O)(OR_(7a))(OR_(7b)); wherein R_(7a) and R_(7b) are each        independently selected from the group consisting of a) hydrogen;        and b) unsubstituted or substituted —C₁-C₈ alkyl;    -   4) —P(O)(OR_(7a))—O—P(O)(OR_(7b))(OR_(7c)); wherein R_(7a) and        R_(7b) are previously defined; R_(7c) is selected from the group        consisting of a) hydrogen; and b) unsubstituted or substituted        —C₁-C₈ alkyl;    -   5) —P(O)(OR_(7a))—O—P(O)(OR_(7b))—O—P(O)(OR_(7c))(OR_(7d));        wherein R_(7a), R_(7b) and R_(7c) are previously defined; R_(7d)        is selected from the group consisting of a) hydrogen; b)        unsubstituted or substituted —C₁-C₈ alkyl;    -   6)

where X is O or S; R₉ is R₇ wherein R₇ is previously defined; R₁₀, R₁₁and R₁₂ are each independently selected from the group consisting of: a)hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl; c) R₁₁ ishydrogen, R₁₂ and R₁₀ taken together with the nitrogen which R₁₀ isattached to form a heterocyclic ring; d) R₁₁ and R₁₂ taken together withthe carbon which they are attached form a ring; R₁₃ is hydrogen or R₇,wherein R₇ is previously defined; and

-   -   7)

where X is O or S; n is 1-4; R_(8a) and R_(8b) are as previouslydefined; R₁₄ is hydrogen or —(CO)—R₇, wherein R₇ is as previouslydefined;

-   -   8) Or, R₁ and R₃ are taken together to form

where X is O or S; and R₁₅ is selected from the group consisting of a)hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl; c) substitutedor unsubstituted —C₂-C₈ alkenyl; d) substituted or unsubstituted —C₂-C₈alkynyl; e) substituted or unsubstituted aryl; f) substituted orunsubstituted heteroaryl.

-   R_(ea) is selected from the group consisting of:    -   1) hydrogen;    -   2) halogen;    -   3) Substituted or unsubstituted —C₁-C₈ alkyl;    -   4) Substituted or unsubstituted —C₂-C₈ alkenyl; and    -   5) Substituted or unsubstituted —C₂-C₈ alkynyl;-   R_(2b) and R₄ are independently selected from the group consisting    of:    -   1) hydrogen;    -   2) halogen;    -   3) —CN;    -   4) —N₃; and    -   5) OR₉;    -   R₉ at each occurrence is selected from the group consisting of:        hydrogen, hydroxy protecting group, R₁₀, —C(O)R₁₀, —C(O)OR₁₀,        and —C(O)NR_(11a)R_(11b); wherein R₁₀ at each occurrence is        independently selected from the group consisting of: substituted        or unsubstituted —C₁-C₈ alkyl, substituted or unsubstituted        —C₂-C₈ alkenyl, substituted or unsubstituted —C₂-C₈ alkynyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, and substituted or unsubstituted heterocyclic;        R_(11a) and R_(11b) at each occurrence are each independently        selected from the group consisting of: hydrogen and R₁₀; or        alternatively R_(11a) and R_(11b) taken together with the        nitrogen atom to which they are attached form a heterocyclic        ring;-   R₃ is R₆; wherein R₆ is as previously defined;-   R_(5a) and R_(5b) are independently selected from the group    consisting of:    -   1) hydrogen;    -   2) substituted or unsubstituted —C₁-C₈ alkyl;    -   3) substituted or unsubstituted —C₂-C₈ alkenyl; and    -   4) substituted or unsubstituted —C₂-C₈ alkynyl;    -   or R_(5a) and R_(5b) are taken together with the carbon atom to        which they are attached to form a group selected from —C₃-C₈        cycloalkyl, —C₃-C₈ cycloalkenyl, or —C₃-C₈ cycloalkynyl.

In certain embodiments of the compounds of Formula I, R_(2a) isC₁-C₆-alkyl, preferably methyl; CF₃, F or OH. In certain embodiments ofthe compounds of Formula I, R_(2b) is hydrogen, halogen, —CN, —N₃ or OH,preferably F or OH. In certain embodiments of the compounds of FormulaI, R₄ is hydrogen, halogen or OH, preferably hydrogen. In certainembodiments of the compounds of Formula I, R_(5a) and R_(5b) areindependently hydrogen or C₁-C₆-alkyl or R_(5a) and R_(5b), togetherwith the carbon atom to which they are attached, form a C₃-C₆-cycloalkylgroup. Preferably one of R_(5a) and R_(5b) is methyl and the other ishydrogen; R_(5a) and R_(5b) are both hydrogen; or R_(5a) and R_(5b),together with the carbon atom to which they are attached, form acyclopropyl group. In certain embodiments of the compounds of Formula I,R₉ is aryl, substituted aryl or C₁-C₆-alkyl, preferably phenyl,naphthyl, p-fluorophenyl or isopropyl. R₁₁ is hydrogen, C₁-C₆-alkyl oraryl-C₁-C₃-alkyl, preferably hydrogen, methyl, isopropyl, isobutyl orbenzyl. In certain embodiments of the compounds of Formula I, R₁₂ ishydrogen. In certain embodiments of the compounds of Formula I, R₁₃ isC₁-C₆-alkyl or aryl-C₁-C₃-alkyl, preferably hydrogen, methyl, isopropyl,isobutyl or benzyl. In certain embodiments of the compounds of FormulaI, R_(2a) is methyl and R_(2b) is OH or F.

In certain embodiments of the compounds of Formula I, R_(2a) isC₁-C₆-alkyl, preferably methyl, CF₃, F or OH, and more preferablymethyl; R_(2b) is hydrogen, halogen, —CN, —N₃ or OH, preferably F or OH;R₄ is hydrogen, halogen or OH, preferably hydrogen; R_(5a) and R_(5b)are independently hydrogen or C₁-C₆-alkyl or R_(5a) and R_(5b), togetherwith the carbon atom to which they are attached, form a C₃-C₆-cycloalkylgroup; preferably one of R_(5a) and R_(5b) is methyl and the other ishydrogen; R_(5a) and R_(5b) are both hydrogen; or R_(5a) and R_(5b),together with the carbon atom to which they are attached, form acyclopropyl group; R₉ is aryl, substituted aryl or C₁-C₆-alkyl,preferably phenyl, naphthyl, p-fluorophenyl or isopropyl; R₁₁ ishydrogen, C₁-C₆-alkyl or aryl-C₁-C₃-alkyl, preferably hydrogen, methyl,isopropyl, isobutyl or benzyl; R₁₂ is hydrogen; and R₁₃ is C₁-C₆-alkylor aryl-C₁-C₃-alkyl, preferably hydrogen, methyl, isopropyl, isobutyl orbenzyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt form, stereoisomer, tautomer, solvate,or combination thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.

In yet another embodiment, the present invention provides a method ofinhibiting the replication of an RNA or DNA containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or a combination of compounds of the present invention, or apharmaceutically acceptable salt, stereoisomer, tautomer, solvate, orcombination thereof. Particularly, this invention is directed to methodsof inhibiting the replication of HCV, HBV and/or HIV.

In still another embodiment, the present invention provides a method oftreating or preventing infection caused by an RNA or DNA-containingvirus comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt form, stereoisomer, or tautomer, solvate, or combination thereof.Particularly, this invention is directed to methods of treating orpreventing infection caused by HCV, HBV and/or HIV.

Yet another embodiment of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt form, stereoisomer or tautomer, solvate,or combination thereof, as defined hereinafter, in the preparation of amedicament for the treatment or prevention of infection caused by RNA orDNA-containing virus, specifically HCV, HBV and/or HIV.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by FormulaI as described above, or a pharmaceutically acceptable salt, ester orprodrug thereof.

A second embodiment of the invention is a compound represented byFormula II or a pharmaceutically acceptable salt, ester or prodrugthereof

Wherein, R_(2a), R_(2b), R₃, R, R_(5a) and R_(5b) are as previouslydefined.

Illustrative structures of formula (II) can be represented, but notlimited, by formula (II-1˜II-20):

A third embodiment of the invention is a compound represented by FormulaIII or a pharmaceutically acceptable salt, ester or prodrug thereof.

wherein, R_(2a), R_(2b), R₄, R_(5a), R_(5b), and R₇ are as previouslydefined.

A fourth embodiment of the invention is a compound represented byFormula IV or a pharmaceutically acceptable salt, ester or prodrugthereof, alone or in combination with a pharmaceutically acceptablecarrier or excipient.

wherein, R_(2a), R_(2b), R₃, R₄, R_(5a), R_(5b), R₉, R₁₀, R₁₁, R₁₂, andR₁₃ are as previously defined. X is O or S.Illustrative structures of formula (IV) can be represented, but notlimited, by formula (IV-1˜IV-12):

wherein, R_(2a), R_(2b), R_(5a), and R_(5b) are as previously defined.

A fifth embodiment of the invention is a compound represented by FormulaV or a pharmaceutically acceptable salt, ester or prodrug thereof.

wherein, R_(2a), R_(2b), R₃, R₄, R_(5a), R_(5b), R_(8a), R_(8b), and R₁₄are as previously defined. X is O or S.n is 1˜4.

A sixth embodiment of the invention is a compound represented by FormulaVI or a pharmaceutically acceptable salt, ester or prodrug thereof

wherein, R_(2a), R_(2b), R_(5a), R_(5b), and R₁₅ are as previouslydefined. X is O or S.

Compounds of the invention further include compounds of Formula (VII),

and pharmaceutically acceptable salts, esters or prodrugs thereof,wherein R_(2a), R_(2b), R₉, R₁₁, R₁₂ and R₁₃ are as previously defined.Representative compounds of the invention include, but are not limitedto, the following compounds (example 1 to example 200 in Table 1)according to Formula VII, wherein, R_(2a), R_(2b), R₉, R₁₁, R₁₂, and R₁₃are delineated for each example in Table 1.

TABLE 1 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃ 1 Me OH Ph Me H iPr 2 Me OHPh Me H Me 3 Me OH Ph Me H Et 4 Me OH Ph Me H Bn 5 Me OH Ph Me HCH₂CH(CH₃)₂ 6 Me F Ph Me H iPr 7 Me F Ph Me H Me 8 Me F Ph Me H Et 9 MeF Ph Me H Bn 10 Me F Ph Me H CH₂CH(CH₃)₂ 11 Me OH Ph H H iPr 12 Me OH PhH H Me 13 Me OH Ph H H Et 14 Me OH Ph H H Bn 15 Me OH Ph H H CH₂CH(CH₃)₂16 Me F Ph H H iPr 17 Me F Ph H H Me 18 Me F Ph H H Et 19 Me F Ph H H Bn20 Me F Ph H H CH₂CH(CH₃)₂ 21 Me OH Ph iPr H iPr 22 Me OH Ph iPr H Me 23Me OH Ph iPr H Et 24 Me OH Ph iPr H Bn 25 Me OH Ph iPr H CH₂CH(CH₃)₂ 26Me F Ph iPr H iPr 27 Me F Ph iPr H Me 28 Me F Ph iPr H Et 29 Me F Ph iPrH Bn 30 Me F Ph iPr H CH₂CH(CH₃)₂ 31 Me OH Ph CH₂CH(CH₃)₂ H iPr 32 Me OHPh CH₂CH(CH₃)₂ H Me 33 Me OH Ph CH₂CH(CH₃)₂ H Et 34 Me OH Ph CH₂CH(CH₃)₂H Bn 35 Me OH Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 36 Me F Ph CH₂CH(CH₃)₂ H iPr37 Me F Ph CH₂CH(CH₃)₂ H Me 38 Me F Ph CH₂CH(CH₃)₂ H Et 39 Me F PhCH₂CH(CH₃)₂ H Bn 40 Me F Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 41 Me OH Ph CH₂PhH iPr 42 Me OH Ph CH₂Ph H Me 43 Me OH Ph CH₂Ph H Et 44 Me OH Ph CH₂Ph HBn 45 Me OH Ph CH₂Ph H CH₂CH(CH₃)₂ 46 Me F Ph CH₂Ph H iPr 47 Me F PhCH₂Ph H Me 48 Me F Ph CH₂Ph H Et 49 Me F Ph CH₂Ph H Bn 50 Me F Ph CH₂PhH CH₂CH(CH₃)₂ 51 Me OH 1-Naphthyl Me H iPr 52 Me OH 1-Naphthyl Me H Me53 Me OH 1-Naphthyl Me H Et 54 Me OH 1-Naphthyl Me H Bn 55 Me OH1-Naphthyl Me H CH₂CH(CH₃)₂ 56 Me F 1-Naphthyl Me H iPr 57 Me F1-Naphthyl Me H Me 58 Me F 1-Naphthyl Me H Et 59 Me F 1-Naphthyl Me H Bn60 Me F 1-Naphthyl Me H CH₂CH(CH₃)₂ 61 Me OH 1-Naphthyl H H iPr 62 Me OH1-Naphthyl H H Me 63 Me OH 1-Naphthyl H H Et 64 Me OH 1-Naphthyl H H Bn65 Me OH 1-Naphthyl H H CH₂CH(CH₃)₂ 66 Me F 1-Naphthyl H H iPr 67 Me F1-Naphthyl H H Me 68 Me F 1-Naphthyl H H Et 69 Me F 1-Naphthyl H H Bn 70Me F 1-Naphthyl H H CH₂CH(CH₃)₂ 71 Me OH 1-Naphthyl iPr H iPr 72 Me OH1-Naphthyl iPr H Me 73 Me OH 1-Naphthyl iPr H Et 74 Me OH 1-Naphthyl iPrH Bn 75 Me OH 1-Naphthyl iPr H CH₂CH(CH₃)₂ 76 Me F 1-Naphthyl iPr H iPr77 Me F 1-Naphthyl iPr H Me 78 Me F 1-Naphthyl iPr H Et 79 Me F1-Naphthyl iPr H Bn 80 Me F 1-Naphthyl iPr H CH₂CH(CH₃)₂ 81 Me OH1-Naphthyl CH₂CH(CH₃)₂ H iPr 82 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Me 83 MeOH 1-Naphthyl CH₂CH(CH₃)₂ H Et 84 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Bn 85Me OH 1-Naphthyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 86 Me F 1-NaphthylCH₂CH(CH₃)₂ H iPr 87 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Me 88 Me F 1-NaphthylCH₂CH(CH₃)₂ H Et 89 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Bn 90 Me F 1-NaphthylCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 91 Me OH 1-Naphthyl CH₂Ph H iPr 92 Me OH1-Naphthyl CH₂Ph H Me 93 Me OH 1-Naphthyl CH₂Ph H Et 94 Me OH 1-NaphthylCH₂Ph H Bn 95 Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 96 Me F 1-NaphthylCH₂Ph H iPr 97 Me F 1-Naphthyl CH₂Ph H Me 98 Me F 1-Naphthyl CH₂Ph H Et99 Me F 1-Naphthyl CH₂Ph H Bn 100 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂101 Me OH p-F-Phenyl Me H iPr 102 Me OH p-F-Phenyl Me H Me 103 Me OHp-F-Phenyl Me H Et 104 Me OH p-F-Phenyl Me H Bn 105 Me OH p-F-Phenyl MeH CH₂CH(CH₃)₂ 106 Me F p-F-Phenyl Me H iPr 107 Me F p-F-Phenyl Me H Me108 Me F p-F-Phenyl Me H Et 109 Me F p-F-Phenyl Me H Bn 110 Me Fp-F-Phenyl Me H CH₂CH(CH₃)₂ 111 Me OH p-F-Phenyl H H iPr 112 Me OHp-F-Phenyl H H Me 113 Me OH p-F-Phenyl H H Et 114 Me OH p-F-Phenyl H HBn 115 Me OH p-F-Phenyl H H CH₂CH(CH₃)₂ 116 Me F p-F-Phenyl H H iPr 117Me F p-F-Phenyl H H Me 118 Me F p-F-Phenyl H H Et 119 Me F p-F-Phenyl HH Bn 120 Me F p-F-Phenyl H H CH₂CH(CH₃)₂ 121 Me OH p-F-Phenyl iPr H iPr122 Me OH p-F-Phenyl iPr H Me 123 Me OH p-F-Phenyl iPr H Et 124 Me OHp-F-Phenyl iPr H Bn 125 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 126 Me Fp-F-Phenyl iPr H iPr 127 Me F p-F-Phenyl iPr H Me 128 Me F p-F-PhenyliPr H Et 129 Me F p-F-Phenyl iPr H Bn 130 Me F p-F-Phenyl iPr HCH₂CH(CH₃)₂ 131 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H iPr 132 Me OH p-F-PhenylCH₂CH(CH₃)₂ H Me 133 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 134 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H Bn 135 Me OH p-F-Phenyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 136 Me F p-F-Phenyl CH₂CH(CH₃)₂ H iPr 137 Me F p-F-PhenylCH₂CH(CH₃)₂ H Me 138 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Et 139 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Bn 140 Me F p-F-Phenyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 141 Me OH p-F-Phenyl CH₂Ph H iPr 142 Me OH p-F-Phenyl CH₂PhH Me 143 Me OH p-F-Phenyl CH₂Ph H Et 144 Me OH p-F-Phenyl CH₂Ph H Bn 145Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 146 Me F p-F-Phenyl CH₂Ph H iPr 147Me F p-F-Phenyl CH₂Ph H Me 148 Me F p-F-Phenyl CH₂Ph H Et 149 Me Fp-F-Phenyl CH₂Ph H Bn 150 Me F p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 151 Me OHiPr Me H iPr 152 Me OH iPr Me H Me 153 Me OH iPr Me H Et 154 Me OH iPrMe H Bn 155 Me OH iPr Me H CH₂CH(CH₃)₂ 156 Me F iPr Me H iPr 157 Me FiPr Me H Me 158 Me F iPr Me H Et 159 Me F iPr Me H Bn 160 Me F iPr Me HCH₂CH(CH₃)₂ 161 Me OH iPr H H iPr 162 Me OH iPr H H Me 163 Me OH iPr H HEt 164 Me OH iPr H H Bn 165 Me OH iPr H H CH₂CH(CH₃)₂ 166 Me F iPr H HiPr 167 Me F iPr H H Me 168 Me F iPr H H Et 169 Me F iPr H H Bn 170 Me FiPr H H CH₂CH(CH₃)₂ 171 Me OH iPr iPr H iPr 172 Me OH iPr iPr H Me 173Me OH iPr iPr H Et 174 Me OH iPr iPr H Bn 175 Me OH iPr iPr HCH₂CH(CH₃)₂ 176 Me F iPr iPr H iPr 177 Me F iPr iPr H Me 178 Me F iPriPr H Et 179 Me F iPr iPr H Bn 180 Me F iPr iPr H CH₂CH(CH₃)₂ 181 Me OHiPr CH₂CH(CH₃)₂ H iPr 182 Me OH iPr CH₂CH(CH₃)₂ H Me 183 Me OH iPrCH₂CH(CH₃)₂ H Et 184 Me OH iPr CH₂CH(CH₃)₂ H Bn 185 Me OH iPrCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 186 Me F iPr CH₂CH(CH₃)₂ H iPr 187 Me F iPrCH₂CH(CH₃)₂ H Me 188 Me F iPr CH₂CH(CH₃)₂ H Et 189 Me F iPr CH₂CH(CH₃)₂H Bn 190 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 191 Me OH iPr CH₂Ph H iPr192 Me OH iPr CH₂Ph H Me 193 Me OH iPr CH₂Ph H Et 194 Me OH iPr CH₂Ph HBn 195 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 196 Me F iPr CH₂Ph H iPr 197 Me FiPr CH₂Ph H Me 198 Me F iPr CH₂Ph H Et 199 Me F iPr CH₂Ph H Bn 200 Me FiPr CH₂Ph H CH₂CH(CH₃)₂.

Compounds of the invention further include compounds of Formula (VIII),

and pharmaceutically acceptable salts, esters or prodrugs thereof,wherein R_(2a), R_(2b), R₉, R₁₁, R₁₂ and R₁₃ are as previously defined.Representative compounds of the invention include, but are not limitedto, the following compounds (example 201 to example 400 in Table 2)according to Formula VIII, wherein, R_(2a), R_(2b), R₉, R₁₁, R₁₂, andR₁₃ are delineated for each example in Table 2.

TABLE 2 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃ 201 Me OH Ph Me H iPr 202Me OH Ph Me H Me 203 Me OH Ph Me H Et 204 Me OH Ph Me H Bn 205 Me OH PhMe H CH₂CH(CH₃)₂ 206 Me F Ph Me H iPr 207 Me F Ph Me H Me 208 Me F Ph MeH Et 209 Me F Ph Me H Bn 210 Me F Ph Me H CH₂CH(CH₃)₂ 211 Me OH Ph H HiPr 212 Me OH Ph H H Me 213 Me OH Ph H H Et 214 Me OH Ph H H Bn 215 MeOH Ph H H CH₂CH(CH₃)₂ 216 Me F Ph H H iPr 217 Me F Ph H H Me 218 Me F PhH H Et 219 Me F Ph H H Bn 220 Me F Ph H H CH₂CH(CH₃)₂ 221 Me OH Ph iPr HiPr 222 Me OH Ph iPr H Me 223 Me OH Ph iPr H Et 224 Me OH Ph iPr H Bn225 Me OH Ph iPr H CH₂CH(CH₃)₂ 226 Me F Ph iPr H iPr 227 Me F Ph iPr HMe 228 Me F Ph iPr H Et 229 Me F Ph iPr H Bn 230 Me F Ph iPr HCH₂CH(CH₃)₂ 231 Me OH Ph CH₂CH(CH₃)₂ H iPr 232 Me OH Ph CH₂CH(CH₃)₂ H Me233 Me OH Ph CH₂CH(CH₃)₂ H Et 234 Me OH Ph CH₂CH(CH₃)₂ H Bn 235 Me OH PhCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 236 Me F Ph CH₂CH(CH₃)₂ H iPr 237 Me F PhCH₂CH(CH₃)₂ H Me 238 Me F Ph CH₂CH(CH₃)₂ H Et 239 Me F Ph CH₂CH(CH₃)₂ HBn 240 Me F Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 241 Me OH Ph CH₂Ph H iPr 242 MeOH Ph CH₂Ph H Me 243 Me OH Ph CH₂Ph H Et 244 Me OH Ph CH₂Ph H Bn 245 MeOH Ph CH₂Ph H CH₂CH(CH₃)₂ 246 Me F Ph CH₂Ph H iPr 247 Me F Ph CH₂Ph H Me248 Me F Ph CH₂Ph H Et 249 Me F Ph CH₂Ph H Bn 250 Me F Ph CH₂Ph HCH₂CH(CH₃)₂ 251 Me OH 1-Naphthyl Me H iPr 252 Me OH 1-Naphthyl Me H Me253 Me OH 1-Naphthyl Me H Et 254 Me OH 1-Naphthyl Me H Bn 255 Me OH1-Naphthyl Me H CH₂CH(CH₃)₂ 256 Me F 1-Naphthyl Me H iPr 257 Me F1-Naphthyl Me H Me 258 Me F 1-Naphthyl Me H Et 259 Me F 1-Naphthyl Me HBn 260 Me F 1-Naphthyl Me H CH₂CH(CH₃)₂ 261 Me OH 1-Naphthyl H H iPr 262Me OH 1-Naphthyl H H Me 263 Me OH 1-Naphthyl H H Et 264 Me OH 1-NaphthylH H Bn 265 Me OH 1-Naphthyl H H CH₂CH(CH₃)₂ 266 Me F 1-Naphthyl H H iPr267 Me F 1-Naphthyl H H Me 268 Me F 1-Naphthyl H H Et 269 Me F1-Naphthyl H H Bn 270 Me F 1-Naphthyl H H CH₂CH(CH₃)₂ 271 Me OH1-Naphthyl iPr H iPr 272 Me OH 1-Naphthyl iPr H Me 273 Me OH 1-NaphthyliPr H Et 274 Me OH 1-Naphthyl iPr H Bn 275 Me OH 1-Naphthyl iPr HCH₂CH(CH₃)₂ 276 Me F 1-Naphthyl iPr H iPr 277 Me F 1-Naphthyl iPr H Me278 Me F 1-Naphthyl iPr H Et 279 Me F 1-Naphthyl iPr H Bn 280 Me F1-Naphthyl iPr H CH₂CH(CH₃)₂ 281 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H iPr 282Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Me 283 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Et284 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Bn 285 Me OH 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 286 Me F 1-Naphthyl CH₂CH(CH₃)₂ H iPr 287 Me F 1-NaphthylCH₂CH(CH₃)₂ H Me 288 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Et 289 Me F1-Naphthyl CH₂CH(CH₃)₂ H Bn 290 Me F 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 291 Me OH 1-Naphthyl CH₂Ph H iPr 292 Me OH 1-Naphthyl CH₂PhH Me 293 Me OH 1-Naphthyl CH₂Ph H Et 294 Me OH 1-Naphthyl CH₂Ph H Bn 295Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 296 Me F 1-Naphthyl CH₂Ph H iPr 297Me F 1-Naphthyl CH₂Ph H Me 298 Me F 1-Naphthyl CH₂Ph H Et 299 Me F1-Naphthyl CH₂Ph H Bn 300 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 301 Me OHp-F-Phenyl Me H iPr 302 Me OH p-F-Phenyl Me H Me 303 Me OH p-F-Phenyl MeH Et 304 Me OH p-F-Phenyl Me H Bn 305 Me OH p-F-Phenyl Me H CH₂CH(CH₃)₂306 Me F p-F-Phenyl Me H iPr 307 Me F p-F-Phenyl Me H Me 308 Me Fp-F-Phenyl Me H Et 309 Me F p-F-Phenyl Me H Bn 310 Me F p-F-Phenyl Me HCH₂CH(CH₃)₂ 311 Me OH p-F-Phenyl H H iPr 312 Me OH p-F-Phenyl H H Me 313Me OH p-F-Phenyl H H Et 314 Me OH p-F-Phenyl H H Bn 315 Me OH p-F-PhenylH H CH₂CH(CH₃)₂ 316 Me F p-F-Phenyl H H iPr 317 Me F p-F-Phenyl H H Me318 Me F p-F-Phenyl H H Et 319 Me F p-F-Phenyl H H Bn 320 Me Fp-F-Phenyl H H CH₂CH(CH₃)₂ 321 Me OH p-F-Phenyl iPr H iPr 322 Me OHp-F-Phenyl iPr H Me 323 Me OH p-F-Phenyl iPr H Et 324 Me OH p-F-PhenyliPr H Bn 325 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 326 Me F p-F-Phenyl iPrH iPr 327 Me F p-F-Phenyl iPr H Me 328 Me F p-F-Phenyl iPr H Et 329 Me Fp-F-Phenyl iPr H Bn 330 Me F p-F-Phenyl iPr H CH₂CH(CH₃)₂ 331 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H iPr 332 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Me 333Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 334 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Bn335 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 336 Me F p-F-PhenylCH₂CH(CH₃)₂ H iPr 337 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Me 338 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Et 339 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Bn 340 MeF p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 341 Me OH p-F-Phenyl CH₂Ph H iPr342 Me OH p-F-Phenyl CH₂Ph H Me 343 Me OH p-F-Phenyl CH₂Ph H Et 344 MeOH p-F-Phenyl CH₂Ph H Bn 345 Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 346 MeF p-F-Phenyl CH₂Ph H iPr 347 Me F p-F-Phenyl CH₂Ph H Me 348 Me Fp-F-Phenyl CH₂Ph H Et 349 Me F p-F-Phenyl CH₂Ph H Bn 350 Me F p-F-PhenylCH₂Ph H CH₂CH(CH₃)₂ 351 Me OH iPr Me H iPr 352 Me OH iPr Me H Me 353 MeOH iPr Me H Et 354 Me OH iPr Me H Bn 355 Me OH iPr Me H CH₂CH(CH₃)₂ 356Me F iPr Me H iPr 357 Me F iPr Me H Me 358 Me F iPr Me H Et 359 Me F iPrMe H Bn 360 Me F iPr Me H CH₂CH(CH₃)₂ 361 Me OH iPr H H iPr 362 Me OHiPr H H Me 363 Me OH iPr H H Et 364 Me OH iPr H H Bn 365 Me OH iPr H HCH₂CH(CH₃)₂ 366 Me F iPr H H iPr 367 Me F iPr H H Me 368 Me F iPr H H Et369 Me F iPr H H Bn 370 Me F iPr H H CH₂CH(CH₃)₂ 371 Me OH iPr iPr H iPr372 Me OH iPr iPr H Me 373 Me OH iPr iPr H Et 374 Me OH iPr iPr H Bn 375Me OH iPr iPr H CH₂CH(CH₃)₂ 376 Me F iPr iPr H iPr 377 Me F iPr iPr H Me378 Me F iPr iPr H Et 379 Me F iPr iPr H Bn 380 Me F iPr iPr HCH₂CH(CH₃)₂ 381 Me OH iPr CH₂CH(CH₃)₂ H iPr 382 Me OH iPr CH₂CH(CH₃)₂ HMe 383 Me OH iPr CH₂CH(CH₃)₂ H Et 384 Me OH iPr CH₂CH(CH₃)₂ H Bn 385 MeOH iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 386 Me F iPr CH₂CH(CH₃)₂ H iPr 387 Me FiPr CH₂CH(CH₃)₂ H Me 388 Me F iPr CH₂CH(CH₃)₂ H Et 389 Me F iPrCH₂CH(CH₃)₂ H Bn 390 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 391 Me OH iPrCH₂Ph H iPr 392 Me OH iPr CH₂Ph H Me 393 Me OH iPr CH₂Ph H Et 194 Me OHiPr CH₂Ph H Bn 395 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 396 Me F iPr CH₂Ph HiPr 397 Me F iPr CH₂Ph H Me 398 Me F iPr CH₂Ph H Et 399 Me F iPr CH₂Ph HBn 400 Me F iPr CH₂Ph H CH₂CH(CH₃)₂.

Compounds of the invention further include compounds of Formula (IX),

and pharmaceutically acceptable salts, esters or prodrugs thereof,wherein R_(2a), R_(2b), R₉, R₁₁, R₁₂ and R₁₃ are as previously defined.Representative compounds of the invention include, but are not limitedto, the following compounds (example 401 to example 600 in Table 3)according to Formula IX, wherein, R_(2a), R_(2b), R₉, R₁₁, R₁₂, and R₁₃are delineated for each example in Table 3.

TABLE 3 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃ 401 Me OH Ph Me H iPr 402Me OH Ph Me H Me 403 Me OH Ph Me H Et 404 Me OH Ph Me H Bn 405 Me OH PhMe H CH₂CH(CH₃)₂ 406 Me F Ph Me H iPr 407 Me F Ph Me H Me 408 Me F Ph MeH Et 409 Me F Ph Me H Bn 410 Me F Ph Me H CH₂CH(CH₃)₂ 411 Me OH Ph H HiPr 412 Me OH Ph H H Me 413 Me OH Ph H H Et 414 Me OH Ph H H Bn 415 MeOH Ph H H CH₂CH(CH₃)₂ 416 Me F Ph H H iPr 417 Me F Ph H H Me 418 Me F PhH H Et 419 Me F Ph H H Bn 420 Me F Ph H H CH₂CH(CH₃)₂ 421 Me OH Ph iPr HiPr 422 Me OH Ph iPr H Me 423 Me OH Ph iPr H Et 424 Me OH Ph iPr H Bn425 Me OH Ph iPr H CH₂CH(CH₃)₂ 426 Me F Ph iPr H iPr 427 Me F Ph iPr HMe 428 Me F Ph iPr H Et 429 Me F Ph iPr H Bn 430 Me F Ph iPr HCH₂CH(CH₃)₂ 431 Me OH Ph CH₂CH(CH₃)₂ H iPr 432 Me OH Ph CH₂CH(CH₃)₂ H Me433 Me OH Ph CH₂CH(CH₃)₂ H Et 434 Me OH Ph CH₂CH(CH₃)₂ H Bn 435 Me OH PhCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 436 Me F Ph CH₂CH(CH₃)₂ H iPr 437 Me F PhCH₂CH(CH₃)₂ H Me 438 Me F Ph CH₂CH(CH₃)₂ H Et 439 Me F Ph CH₂CH(CH₃)₂ HBn 440 Me F Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 441 Me OH Ph CH₂Ph H iPr 442 MeOH Ph CH₂Ph H Me 443 Me OH Ph CH₂Ph H Et 444 Me OH Ph CH₂Ph H Bn 445 MeOH Ph CH₂Ph H CH₂CH(CH₃)₂ 446 Me F Ph CH₂Ph H iPr 447 Me F Ph CH₂Ph H Me448 Me F Ph CH₂Ph H Et 449 Me F Ph CH₂Ph H Bn 450 Me F Ph CH₂Ph HCH₂CH(CH₃)₂ 451 Me OH 1-Naphthyl Me H iPr 452 Me OH 1-Naphthyl Me H Me453 Me OH 1-Naphthyl Me H Et 454 Me OH 1-Naphthyl Me H Bn 455 Me OH1-Naphthyl Me H CH₂CH(CH₃)₂ 456 Me F 1-Naphthyl Me H iPr 457 Me F1-Naphthyl Me H Me 458 Me F 1-Naphthyl Me H Et 459 Me F 1-Naphthyl Me HBn 460 Me F 1-Naphthyl Me H CH₂CH(CH₃)₂ 461 Me OH 1-Naphthyl H H iPr 462Me OH 1-Naphthyl H H Me 463 Me OH 1-Naphthyl H H Et 464 Me OH 1-NaphthylH H Bn 465 Me OH 1-Naphthyl H H CH₂CH(CH₃)₂ 466 Me F 1-Naphthyl H H iPr467 Me F 1-Naphthyl H H Me 468 Me F 1-Naphthyl H H Et 469 Me F1-Naphthyl H H Bn 470 Me F 1-Naphthyl H H CH₂CH(CH₃)₂ 471 Me OH1-Naphthyl iPr H iPr 472 Me OH 1-Naphthyl iPr H Me 473 Me OH 1-NaphthyliPr H Et 474 Me OH 1-Naphthyl iPr H Bn 475 Me OH 1-Naphthyl iPr HCH₂CH(CH₃)₂ 476 Me F 1-Naphthyl iPr H iPr 477 Me F 1-Naphthyl iPr H Me478 Me F 1-Naphthyl iPr H Et 479 Me F 1-Naphthyl iPr H Bn 480 Me F1-Naphthyl iPr H CH₂CH(CH₃)₂ 481 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H iPr 482Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Me 483 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Et484 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Bn 485 Me OH 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 486 Me F 1-Naphthyl CH₂CH(CH₃)₂ H iPr 487 Me F 1-NaphthylCH₂CH(CH₃)₂ H Me 488 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Et 489 Me F1-Naphthyl CH₂CH(CH₃)₂ H Bn 490 Me F 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 491 Me OH 1-Naphthyl CH₂Ph H iPr 492 Me OH 1-Naphthyl CH₂PhH Me 493 Me OH 1-Naphthyl CH₂Ph H Et 494 Me OH 1-Naphthyl CH₂Ph H Bn 495Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 496 Me F 1-Naphthyl CH₂Ph H iPr 497Me F 1-Naphthyl CH₂Ph H Me 498 Me F 1-Naphthyl CH₂Ph H Et 499 Me F1-Naphthyl CH₂Ph H Bn 500 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 501 Me OHp-F-Phenyl Me H iPr 502 Me OH p-F-Phenyl Me H Me 503 Me OH p-F-Phenyl MeH Et 504 Me OH p-F-Phenyl Me H Bn 505 Me OH p-F-Phenyl Me H CH₂CH(CH₃)₂506 Me F p-F-Phenyl Me H iPr 507 Me F p-F-Phenyl Me H Me 508 Me Fp-F-Phenyl Me H Et 509 Me F p-F-Phenyl Me H Bn 510 Me F p-F-Phenyl Me HCH₂CH(CH₃)₂ 511 Me OH p-F-Phenyl H H iPr 512 Me OH p-F-Phenyl H H Me 513Me OH p-F-Phenyl H H Et 514 Me OH p-F-Phenyl H H Bn 515 Me OH p-F-PhenylH H CH₂CH(CH₃)₂ 516 Me F p-F-Phenyl H H iPr 517 Me F p-F-Phenyl H H Me518 Me F p-F-Phenyl H H Et 519 Me F p-F-Phenyl H H Bn 520 Me Fp-F-Phenyl H H CH₂CH(CH₃)₂ 521 Me OH p-F-Phenyl iPr H iPr 522 Me OHp-F-Phenyl iPr H Me 523 Me OH p-F-Phenyl iPr H Et 524 Me OH p-F-PhenyliPr H Bn 525 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 526 Me F p-F-Phenyl iPrH iPr 527 Me F p-F-Phenyl iPr H Me 528 Me F p-F-Phenyl iPr H Et 529 Me Fp-F-Phenyl iPr H Bn 530 Me F p-F-Phenyl iPr H CH₂CH(CH₃)₂ 531 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H iPr 532 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Me 533Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 534 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Bn535 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 536 Me F p-F-PhenylCH₂CH(CH₃)₂ H iPr 537 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Me 538 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Et 539 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Bn 540 MeF p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 541 Me OH p-F-Phenyl CH₂Ph H iPr542 Me OH p-F-Phenyl CH₂Ph H Me 543 Me OH p-F-Phenyl CH₂Ph H Et 544 MeOH p-F-Phenyl CH₂Ph H Bn 545 Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 546 MeF p-F-Phenyl CH₂Ph H iPr 547 Me F p-F-Phenyl CH₂Ph H Me 548 Me Fp-F-Phenyl CH₂Ph H Et 549 Me F p-F-Phenyl CH₂Ph H Bn 550 Me F p-F-PhenylCH₂Ph H CH₂CH(CH₃)₂ 551 Me OH iPr Me H iPr 552 Me OH iPr Me H Me 553 MeOH iPr Me H Et 554 Me OH iPr Me H Bn 555 Me OH iPr Me H CH₂CH(CH₃)₂ 556Me F iPr Me H iPr 557 Me F iPr Me H Me 558 Me F iPr Me H Et 559 Me F iPrMe H Bn 560 Me F iPr Me H CH₂CH(CH₃)₂ 561 Me OH iPr H H iPr 562 Me OHiPr H H Me 563 Me OH iPr H H Et 564 Me OH iPr H H Bn 565 Me OH iPr H HCH₂CH(CH₃)₂ 566 Me F iPr H H iPr 567 Me F iPr H H Me 568 Me F iPr H H Et569 Me F iPr H H Bn 570 Me F iPr H H CH₂CH(CH₃)₂ 571 Me OH iPr iPr H iPr572 Me OH iPr iPr H Me 573 Me OH iPr iPr H Et 574 Me OH iPr iPr H Bn 575Me OH iPr iPr H CH₂CH(CH₃)₂ 576 Me F iPr iPr H iPr 577 Me F iPr iPr H Me578 Me F iPr iPr H Et 579 Me F iPr iPr H Bn 580 Me F iPr iPr HCH₂CH(CH₃)₂ 581 Me OH iPr CH₂CH(CH₃)₂ H iPr 582 Me OH iPr CH₂CH(CH₃)₂ HMe 583 Me OH iPr CH₂CH(CH₃)₂ H Et 584 Me OH iPr CH₂CH(CH₃)₂ H Bn 585 MeOH iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 586 Me F iPr CH₂CH(CH₃)₂ H iPr 587 Me FiPr CH₂CH(CH₃)₂ H Me 588 Me F iPr CH₂CH(CH₃)₂ H Et 589 Me F iPrCH₂CH(CH₃)₂ H Bn 590 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 591 Me OH iPrCH₂Ph H iPr 592 Me OH iPr CH₂Ph H Me 593 Me OH iPr CH₂Ph H Et 594 Me OHiPr CH₂Ph H Bn 595 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 596 Me F iPr CH₂Ph HiPr 597 Me F iPr CH₂Ph H Me 598 Me F iPr CH₂Ph H Et 599 Me F iPr CH₂Ph HBn 600 Me F iPr CH₂Ph H CH₂CH(CH₃)₂

Compounds of the invention further include compounds of Formula (X),

and pharmaceutically acceptable salts, esters or prodrugs thereof,wherein R_(2a), R_(2b), R_(5a), R_(5b), R_(8a) and R_(8b) are aspreviously defined. Representative compounds of the invention include,but are not limited to, the following compounds (example 601 to example660 in Table 4) according to Formula X, wherein, R_(2a), R_(2b), R_(5a),R_(5b), R_(8a), and R_(8b) are delineated for each example in Table 4.

TABLE 4         Example         R_(2a)         R_(2b)  

601 Me OH PhCH₂NH

602 Me OH PhCH₂NH

603 Me OH PhCH₂NH

604 Me OH ^(i)PrNH

605 Me OH ^(i)PrNH

606 Me OH ^(i)PrNH

607 Me OH ^(t)BuNH

608 Me OH ^(t)BuNH

609 Me OH ^(t)BuNH

610 Me OH

611 Me OH

612 Me OH

613 Me OH

614 Me OH

615 Me OH

616 Me OH

617 Me OH

618 Me OH

619 Me OH NHCH₂CO₂Et

620 Me OH NH CH₂CO₂Et

621 Me OH NH CH₂CO₂Et

622 Me OH NH CH₂CO₂ ^(t)Bu

623 Me OH NH CH₂CO₂ ^(t)Bu

624 Me OH NH CH₂CO₂ ^(t)Bu

625 Me OH NH CH₂CO₂H

626 Me OH NH CH₂CO₂H

627 Me OH NH CH₂CO₂H

628 Me OH NH CH₂CH₂NMe₂

629 Me OH NH CH₂CH₂NMe₂

630 Me OH NH CH₂CH₂NMe₂

631 Me F PhCH₂NH

632 Me F PhCH₂NH

633 Me F PhCH₂NH

634 Me F ^(i)PrNH

635 Me F ^(i)PrNH

636 Me F ^(i)PrNH

637 Me F ^(t)BuNH

638 Me F ^(t)BuNH

639 Me F ^(t)BuNH

640 Me F

641 Me F

642 Me F

643 Me F

644 Me F

645 Me F

646 Me F

647 Me F

648 Me F

649 Me F NHCH₂CO₂Et

650 Me F NH CH₂CO₂Et

651 Me F NH CH₂CO₂Et

652 Me F NH CH₂CO₂ ^(t)Bu

653 Me F NH CH₂CO₂ ^(t)Bu

654 Me F NH CH₂CO₂ ^(t)Bu

655 Me F NH CH₂CO₂H

656 Me F NH CH₂CO₂H

657 Me F NH CH₂CO₂H

658 Me F NH CH₂CH₂NMe₂

659 Me F NH CH₂CH₂NMe₂

660 Me F NH CH₂CH₂NMe₂

The term “compound”, as used herein in reference to the compounds ofFormulas I-X, refers to a collection of molecules of identical molecularstructure, except for isotopic variation. Atoms within the compoundswhich are not designated as a specific isotope can be any stable isotopeof the indicated element. Typically, the isotopic distribution of eachsuch atom will correspond substantially to the natural isotopicabundance for that element. The designation of an atom as deuterium inthe compounds of the invention indicates that this position is enrichedwith deuterium at a level which is significantly greater than thenatural abundance of this isotope. For example, in preferred compoundsof the invention, the designation of an atom as deuterium signifies thatthis position is deuterated in at least 5% of the molecules. Preferably,such a position is deuterated in at least 10, 20, 30, 40 or 50% of themolecules. In certain embodiments, such a position is deuterated in 60,70, 80, 90 or 95% of the molecules. The compounds of the invention havetwo atoms designated as deuterium, and in preferred embodiments bothpositions are deuterated in at least 5%, 10%, 25%, 50%, 60%, 75% 80%,90% or 95% of the molecules.

The present invention also features pharmaceutical compositionscomprising a compound of the invention, or a pharmaceutically acceptablesalt, ester or prodrug thereof. In one embodiment, the present inventionfeatures pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, in combination with apharmaceutically acceptable carrier or excipient. In another embodiment,the invention features methods of treating a hepatitis C infection in asubject in need of such treatment with said pharmaceutical composition.

In addition, the present invention features methods of using compoundsof the present invention or pharmaceutically acceptable salts thereof totreat HCV infection. The methods comprise administering to an HCVpatient in need thereof an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetric carbon atoms and may exist in racemic,diastereoisomeric, and optically active forms. It should be understoodthat the compounds encompassed by the present invention are those thatare suitably stable for use as pharmaceutical agent.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, in combination with one or more agents known in the art, with apharmaceutically acceptable carrier or excipient. In the methodsdescribed herein, a compound of the present invention or apharmaceutically acceptable salt thereof can be administered alone, orin combination with one or more other anti-HCV agents, such as HCVpolymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors,CD81 inhibitors, cyclophilin inhibitors, internal ribosome entry site(IRES) inhibitors or any combinations thereof. Interferon, ribavirin orboth can also be included in the treatment. For example, the methodsdescribed herein can further comprise administering to the patientpeginterferon-alpha and ribavirin. Different agents can be administeredsimultaneously or sequentially. The dosing frequency of each agent in atreatment regimen can be the same or different. For instance, a compoundof the invention can be dosed once daily and ribavirin can be dosedtwice daily.

Compounds of the present invention can be administered as the soleactive pharmaceutical agent, or used in combination with one or moreagents to treat or prevent hepatitis C infections or the symptomsassociated with HCV infection. Other agents to be administered incombination with a compound or combination of compounds of the inventioninclude therapies for disease caused by HCV infection that suppressesHCV viral replication by direct or indirect mechanisms. These includeagents such as host immune modulators (for example, interferon-alpha,pegylated interferon-alpha, interferon-beta, interferon-gamma, CpGoligonucleotides and the like), cyclophilins (e.g., Debio 025), orantiviral compounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like). Alsoincluded are cytokines that modulate immune function. Also included arevaccines comprising HCV antigens or antigen adjuvant combinationsdirected against HCV. Also included are agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like. Other agents to be administered incombination with a compound of the present invention include any agentor combination of agents that inhibit the replication of HCV bytargeting proteins of the viral genome involved in the viralreplication. These agents include but are not limited to otherinhibitors of HCV RNA dependent RNA polymerase such as, for example,nucleoside type polymerase inhibitors described in WO0190121(A2), orU.S. Pat. No. 6,348,587B1 or WO0160315 or WO0132153 or non-nucleosideinhibitors such as, for example, benzimidazole polymerase inhibitorsdescribed in EP 1162196A1 or WO0204425 or inhibitors of HCV proteasesuch as, for example, peptidomimetic type inhibitors such as BILN2061and the like or inhibitors of HCV helicase.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents thatinhibit the replication of other viruses for co-infected individuals.These agents include but are not limited to therapies for disease causedby hepatitis B (HBV) infection or therapies for disease caused by humanimmunodeficiency virus (HIV) infection.

Accordingly, one aspect of the invention is directed to a method fortreating or preventing an infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents selected from the group consisting of a host immunemodulator and a second antiviral agent, or a combination thereof, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Examples of the host immune modulator are, but not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant, and said second antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

A further aspect of the invention is directed to a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment an agent orcombination of agents that treat or alleviate symptoms of HCV infectionincluding cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Yet another aspect of the invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the invention, or a pharmaceuticallyacceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, orcombination thereof. An agent that treats patients for disease caused byhepatitis B (HBV) infection may be for example, but not limited thereto,L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV).

Another aspect of the invention provides a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment one or moreagents that treat patients for disease caused by human immunodeficiencyvirus (HIV) infection, with a therapeutically effective amount of acompound or a combination of compounds of the invention, or apharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, saltof a prodrug, or combination thereof. An example of the RNA-containingvirus includes, but not limited to, hepatitis C virus (HCV). Inaddition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt form, stereoisomer, or tautomer, prodrug, salt of aprodrug, or combination thereof, and one or more agents selected fromthe group consisting of a host immune modulator and a second antiviralagent, or a combination thereof, to prepare a medicament for thetreatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Examples of the host immunemodulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound orcompounds of the invention, together with one or more agents as definedherein above, can be employed in pure form or, where such forms exist,in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, orcombination thereof. Alternatively, such combination of therapeuticagents can be administered as a pharmaceutical composition containing atherapeutically effective amount of the compound or combination ofcompounds of interest, or their pharmaceutically acceptable salt form,prodrugs, or salts of the prodrug, in combination with one or moreagents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, further aspect of the invention is directed to a method oftreating or preventing infection caused by an RNA-containing virus,particularly a hepatitis C virus (HCV), comprising administering to apatient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug,salt of a prodrug, or combination thereof, one or more agents as definedhereinabove, and a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to, agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective fordiminishing or preventing the progression of hepatitis C relatedsymptoms or disease. Such agents include but are not limited toimmunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase, inhibitors of another target in the HCVlife cycle and other anti-HCV agents, including but not limited to,ribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals)that are effective to enhance or potentiate the immune system responsein a mammal. Immunomodulatory agents include, but are not limited to,inosine monophosphate dehydrogenase inhibitors such as VX-497(merimepodib, Vertex Pharmaceuticals), class I interferons, class IIinterferons, consensus interferons, asialo-interferons pegylatedinterferons and conjugated interferons, including but not limited to,interferons conjugated with other proteins including but not limited to,human albumin. Class I interferons are a group of interferons that allbind to receptor type I, including both naturally and syntheticallyproduced class I interferons, while class II interferons all bind toreceptor type II. Examples of class I interferons include, but are notlimited to, [alpha]-, [beta]-, [delta]-, [omega]-, and[tau]-interferons, while examples of class II interferons include, butare not limited to, [gamma]-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals)that are effective to inhibit the function of HCV NS3 protease in amammal Inhibitors of HCV NS3 protease include, but are not limited to,those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO2006/000085, WO 2006/007700 and WO 2006/007708 (all by BoehringerIngelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO2005/037214 (Intermune) and WO 2005/051980 (Schering), and thecandidates identified as VX-950, ITMN-191 and SCH 503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals)that are effective to inhibit the function of an HCV polymerase. Suchinhibitors include, but are not limited to, non-nucleoside andnucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors ofHCV polymerase include but are not limited to those compounds describedin: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all byBoehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543(Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (JapanTobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidatesXTL-2125, HCV 796, R-1626 and NM 283.

Inhibitors of another target in the HCV life cycle include agents(compounds or biologicals) that are effective to inhibit the formationand/or replication of HCV other than by inhibiting the function of theHCV NS3 protease. Such agents may interfere with either host or HCVviral mechanisms necessary for the formation and/or replication of HCVInhibitors of another target in the HCV life cycle include, but are notlimited to, entry inhibitors, agents that inhibit a target selected froma helicase, a NS2/3 protease and an internal ribosome entry site (IRES)and agents that interfere with the function of other viral targetsincluding but not limited to, an NS5A protein and an NS4B protein.

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to, humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is combination therapy to treat suchco-infections by co-administering a compound according to the presentinvention with at least one of an HIV inhibitor, an HAV inhibitor and anHBV inhibitor.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, and internal ribosome entry site (IRES).

According to still another embodiment, the present invention includesmethods of treating viral infection such as, but not limited to,hepatitis C infections in a subject in need of such treatment byadministering to said subject an effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt, ester, orprodrug thereof.

According to a further embodiment, the present invention includesmethods of treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject an anti-HCV virally effectiveamount or an inhibitory amount of a pharmaceutical composition of thepresent invention.

An additional embodiment of the present invention includes methods oftreating biological samples by contacting the biological samples withthe compounds of the present invention.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

The term “immune modulator” refers to any substance meant to alter theworking of the humoral or cellular immune system of a subject. Suchimmune modulators include inhibitors of mast cell-mediated inflammation,interferons, interleukins, prostaglandins, steroids, cortico-steroids,colony-stimulating factors, chemotactic factors, etc.

The term “alkyl”, as used herein, refers to a saturated, straight- orbranched-chain hydrocarbongroup. Preferred alkyl radicals include C₁-C₆alkyl and C₁-C₈ alkyl radicals. Examples of C₁-C₆ alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,tert-butyl, neopentyl, n-hexyl groups; and examples of C₁-C₈ alkylgroups include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octylgroups.

The term “alkenyl”, as used herein, denote a monovalent group derivedfrom a hydrocarbon moiety by the removal of a single hydrogen atomwherein the hydrocarbon moiety has at least one carbon-carbon doublebond. Preferred alkenyl groups include C₂-C₆ alkenyl and C₂-C₈ alkenylgroups. Alkenyl groups include, but are not limited to, for example,ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl andthe like.

The term “alkynyl”, as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety by the removal of a single hydrogen atomwherein the hydrocarbon moiety has at least one carbon-carbon triplebond. Preferred alkynyl groups include C₂-C₆ alkynyl and C₂-C₈ alkynylgroups. Representative alkynyl groups include, but are not limited to,for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and thelike.

The term “carbocycle” refers to a saturated (e.g., “cycloalkyl”),partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) orcompletely unsaturated (e.g., “aryl”) ring system containing zeroheteroatom ring atom. “Ring atoms” or “ring members” are the atoms boundtogether to form the ring or rings. Where a carbocycle group is adivalent moiety linking two other elements in a depicted chemicalstructure (such as Z in Formula I_(A)), the carbocycle group can beattached to the two other elements through any two substitutable ringatoms. A C₄-C₆ carbocycle has 4-6 ring atoms.

The term “cycloalkyl”, as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Preferred cycloalkylgroups include C₃-C₈ cycloalkyl and C₃-C₁₂ cycloalkyl groups. Examplesof C₃-C₈-cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; andexamples of C₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, andbicyclo[2.2.2]octyl.

The term “cycloalkenyl” as used herein, denote a monovalent groupderived from a monocyclic or polycyclic carbocyclic ring compound havingat least one carbon-carbon double bond by the removal of a singlehydrogen atom. Preferred cycloalkenyl groups include C₃-C₈ cycloalkenyland C₃-C₁₂ cycloalkenyl groups. Examples of C₃-C₈-cycloalkenyl include,but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples ofC₃-C₁₂-cycloalkenyl include, but not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyland the like.

The term “arylalkyl,” as used herein, refers to a C₁-C₃ alkyl or C₁-C₆alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which at least one ring atom is selected from S, O and N; wherein anyN or S contained within the ring may be optionally oxidized. Preferredheteroaryl groups are monocyclic or bicyclic. Heteroaryl groups include,but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.

The term “heteroarylalkyl,” as used herein, refers to a C₁-C₃ alkyl orC₁-C₆ alkyl residue attached to a heteroaryl ring. Examples include, butare not limited to, pyridinylmethyl, pyrimidinylmethyl and the like.

The term “substituted” as used herein, refers to independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy,thioalkoxy, oxo, -halo-C₁-C₁₂-alkyl, -halo-C₂-C₁₂-alkenyl,-halo-C₂-C₁₂-alkynyl, -halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. It is understoodthat the aryls, heteroaryls, alkyls, and the like can be furthersubstituted. In some cases, each substituent in a substituted moiety isadditionally optionally substituted with one or more groups, each groupbeing independently selected from —F, —Cl, —Br, —I, —OH, —NO₂, —CN, or—NH₂.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group, analicyclic group or a heterocyclic group. An “aliphatic group” isnon-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Such alicyclic groups maybe further substituted.

The term “heterocycloalkyl” and “heterocyclic” can be usedinterchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or 7-memberedring or a bi- or tri-cyclic group fused system, where: (i) each ringcontains between one and three heteroatoms independently selected fromoxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 doublebonds and each 6-membered ring has 0 to 2 double bonds, (iii) thenitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to a benzene ring, and (vi) the remaining ring atomsare carbon atoms which may be optionally oxo-substituted. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, andtetrahydrofuryl. Such heterocyclic groups may be further substituted togive substituted heterocyclic.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, hetoerarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the formulas herein with proper valency.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxy activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques, which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G., S. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxy protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃). Berge, et al. describes pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or separately by reacting the free basefunction with a suitable organic acid. Examples of pharmaceuticallyacceptable salts include, but are not limited to, nontoxic acid additionsalts e.g., salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired bridged macrocyclic products of the presentinvention. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 100 mg/Kg Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, mean a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject(e.g., resulting in at least 10%, preferably at least 50%, morepreferably at least 80%, and most preferably at least 90% or 95%,reduction in viral load). As well understood in the medical arts, ananti-hepatitis C virally effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject (e.g., resulting in at least 10%,preferably at least 50%, more preferably at least 80%, and mostpreferably at least 90% or 95%, reduction in viral load). It isunderstood that when said inhibitory amount of a compound of the presentinvention is administered to a subject it will be at a reasonablebenefit/risk ratio applicable to any medical treatment as determined bya physician. The term “biological sample(s),” as used herein, means asubstance of biological origin intended for administration to a subject.Examples of biological samples include, but are not limited to, bloodand components thereof such as plasma, platelets, subpopulations ofblood cells and the like; organs such as kidney, liver, heart, lung, andthe like; sperm and ova; bone marrow and components thereof; or stemcells. Thus, another embodiment of the present invention is a method oftreating a biological sample by contacting said biological sample withan inhibitory amount of a compound or pharmaceutical composition of thepresent invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. Ingeneral, treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

ACN for acetonitrile;

BME for 2-mercaptoethanol;

BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate;

BzCl for benzoyl chloride;

CDI for carbonyldiimidazole;

COD for cyclooctadiene;

DABCO for 1,4-diazabicyclo[2.2.2]octane;

DAST for diethylaminosulfur trifluoride;

DABCYL for6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;

DBU for 1,8-Diazabicycloundec-7-ene;

DCC for N,N′-dicyclohexylcarbodiimide;

DCM for dichloromethane;

DIAD for diisopropyl azodicarboxylate;

DIBAL-H for diisobutylaluminum hydride;

DIPEA for diisopropyl ethylamine;

DMAP for N,N-dimethylaminopyridine;

DME for ethylene glycol dimethyl ether;

DMEM for Dulbecco's Modified Eagles Media;

DMF for N,N-dimethyl formamide;

DMSO for dimethylsulfoxide;

DSC for N,N′-disuccinimidyl carbonate;

DUPHOS for

EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;

EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimidehydrochloride;

EtOAc for ethyl acetate;

EtOH for ethyl alcohol;

HATU for O(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;

HCl for hydrochloric acid;

Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II);

In for indium;

KHMDS is potassium bis(trimethylsilyl)amide;

Ms for mesyl;

NMM for N-4-methylmorpholine;

NMI for N-methylimidazole;

NMO for N-4-methylmorpholine-N-Oxide;

PyBrOP for Bromo-tri-pyrrolidino-phosphonium hexafluorophosphate;

Ph for phenyl;

RCM for ring-closing metathesis;

RT for reverse transcription;

RT-PCR for reverse transcription-polymerase chain reaction;

TBME for tert-butyl methyl ether;

TEA for triethyl amine;

Tf₂O for trifluoromethanesulfonic anhydride

TFA for trifluoroacetic acid;

THF for tetrahydrofuran;

TLC for thin layer chromatography;

(TMS)₂NH for hexamethyldisilazane

TMSOTf for trimethylsilyl trifluoromethanesulfonate;

TPAP tetrapropylammonium perruthenate;

TPP or PPh₃ for triphenylphosphine;

TrCl for trityl chloride;

DMTrCl for 4,4′-dimethoxytrityl chloride;

tBOC or Boc for tert-butyloxy carbonyl;

Xantphos for 4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene; and

Zhan 1 B for

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

One approach to the synthesis of deuterated compounds of Formula II isexemplified in Scheme 1, wherein R_(2a), R_(2b), R₄, R_(5a), R_(5b) andR₇ is previously defined. The deuterated cytosine I-1 was treated withacylation reagent I-2 in the presence of base such as, but not limitedto, DIEPA, TEA, DMAP, DBU to provide the acylated product I-3. LG₁ isdefined as leaving group such as, but not limited to, —Cl, —Br, —I, —F,—OTs, —OCOCF₃, —OCOCH₃, —OSO₂CF₃, —NR₃ ⁺.

The compound I-5 could be synthesized from the glycosylation betweencompound I-4 and a deuterated base I-3 (or its derivatives such as, butnot limited to the persilylated derivatives) employing a suitablecatalyst such as, but not limited to TMSOTf or SnCl₄ with or withoutpresence of a suitable base. Examples of suitable base includes, but notlimited to, DIEPA, TEA, DMAP, DBU and DABCO. LG₂ is defined as leavinggroup such as, but not limited to, —Cl, —Br, —I, —F, —OTs, —OCOCF₃,—COCH₃, —OSO₂CF₃, —NR₃ ⁺.

The cytosine derivative I-5 could be converted into the uracilderivative of formula III via a deamination process employing a suitableacid such as, but not limited to acetic acid with or without water.

The compound of formula II could be synthesized from the deprotection ofcompound with formula III when treated with a suitable base such as, butnot limited to NH₃ in the presence of alcohol such as, but not limitedto methanol.

The compound of formula IV (R₃═H, X═O) could be synthesized by couplingof nucleoside compound of formula II with phosphoamidate compound II-1in the presence of organic/inorganic base such as, but not limited to,NMI, DIEPA, TEA, DMAP and iPrMgCl, as exemplified in Scheme 2. LG₃ is aleaving group such as, but not limited to, Cl or pentafluorophenoxy.

Another approach to the synthesis of deuterated compound of Formula I isexemplified in Scheme 3. The deuterated compounds Formula (I) could besynthesized from selective deuteration of the base via H-D exchangeprocess employing a suitable catalyst such as, but not limited to, Pd onCarbon, PtO₂, adam's catalyst with or without the presence of H₂, whileD₂O or D₂ gas serving as the deuterium source. (For further details onH-D exchanges see recent publications: Atzrodt et al., Angew. Chem. Int.Ed. 2007, 46, 7744; Földesi et al., Nucleos. Nucleot. Nucl. 2000, 19,1615; Sajiki et al., Synlett 2005, 9, 1385, Sajiki et al., Synthesis2009, 16, 2674; Maeda et al., Tetrahedron Lett. 1975, 19, 1643).

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of Formula VII, wherein R_(2a)=Me, R_(2b)=F, R₉=phenyl, R₁₁=H,R₁₂=Me, R₁₃=iPr,

Step 1A

To a suspension of cytosine-5,6-d₂ 1a-1 (500 mg, 4.464 mmol) in pyridine(6 mL) at 0° C. was added BzCl (1.05 mL, 9.0 mmol) dropwise over 10 min.The resulted mixture was stirred at RT for 4 h, and quenched with MeOH(0.3 mL) and stirred for 10 min. The precipitate was collected byfiltration and washed with EtOH and Et₂O. The residue was dried to givethe product 1a (642 mg, 67%). MS (ESI): m/e 218.11 (M+H). ¹H NMR(DMSO-D₆) δ 11.56 (s, 1H), 11.09 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.6(t, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H),

Step 1B

To a suspension of compound (1a) (64 mg, 0.298 mmol) in chlorobenzene(1.5 mL) was added (NH₄)₂SO₄ (1.2 mg) and hexamethyldisilazane (0.8 mL).The resulted mixture was stirred at 140° C. for 1 h until the mixturebecame a clear solution, and the mixture was concentrated in vacuowithout exposure to air. To this residue was added chlorobenzene (1.5mL) and compound (1b-1) (˜0.447 mmol) in chlorobenzene (1.5 mL)(synthesis of compound (1b-1) see: Steven et al. PCT Int. Appl.2008045419) and SnCl₄ (0.14 ml). The resulted mixture was heated up to80° C. for 4 hrs and diluted with DCM. To the mixture was added NaHCO₃(0.50 g) and celite (0.3 g) and water (84 uL). The resulted mixture washeated up to reflux for 20 min and then filtered. The filtrate wasconcentrated and first purified by CombiFlash (hexane to 80% EtOAc inhexane) followed by crystallization in DCM/PhCl to give the desiredproduct 1b (51 mg). MS (ESI): m/e 574.54 (M+H),

Step 1C

To compound 1b (120 mg, 0.209 mmol) was added AcOH (2.4 mL) and water(0.6 mL), and the resulted mixture was heated up to 100° C. for 14 h.The solvent was removed in vacuo and the residue was triturated with DCMand Et₂O to give compound 1c-1 as white powder (62 mg) after drying. Tothis powder was added NH₃ (3 mL, 7 N in MeOH) and the suspension wasstirred at RT for 14 h until it became a clear solution. The solvent wasremoved in vacuo and the residue was triturated with DCM and Et₂O togive the product 1c (12 mg). ¹H NMR (CD₃OD) δ 6.13 (d, J=18.5 Hz, 1H),3.93-4.04 (m, 3H), 3.81 (d, J=13.5 Hz, 1H), 1.36 (d, J=22.5 Hz, 3H),

Step 1D

To compound 1c (12 mg, 0.0454 mmol) in THF (1.5 mL) at 0° C. was addedtBuMgCl (91 uL, 1.0 M in THF) dropwise and the resulted cloudy solutionwas stirred at RT for 20 min. To this mixture was added compound 1d-1(37 mg, 0.817 mmol) in THF (1.0 mL) dropwise and the resulted mixturewas stirred at RT for 14 h (for synthesis of compound 1d-1 see Ross etal. US 2011/0251152 A1). The resulted mixture was quenched with NaHCO₃(aq) and the mixture was concentrated in vacuo. The residue was purifiedby flash column chromatography (DCM to 8% MeOH in DCM) to afford theproduct Example 1 (8 mg). MS (ESI): m/e 532.1 (M+H). ¹H NMR (CDCl₃) δ8.73 (s, 1H), 7.35-7.40 (m, 2H), 7.17-7.26 (m, 3H), 6.19 (d, J=18.0 Hz,1H), 4.99-5.07 (m, 1H), 4.51-4.59 (m, 1H), 4.42-4.50 (m, 1H), 4.10-4.15(m, 1H), 3.89-4.00 (m, 2H), 1.42 (d, J=22.5 Hz, 6H), 1.34-1.38 (m, 3H),1.25 (d, J=7.0 Hz, 6H).

Biological Activity

1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolatedfrom colonies as described by Lohman et al. (Lohman et al. (1999)Science 285: 110-113, expressly incorporated by reference in itsentirety) and used for all experiments. One of the HCV replicon celllines (strain Conl, genotype 1b) has the nucleic acid sequence set forthin EMBL Accession No.: AJ242651, the coding sequence of which is fromnucleotides 1801 to 8406. Another replicon cell line (strain H77,genotype 1a) was constructed as described by Yi et. al. (Yi et. al.(2004) Journal of Virology 78(15):7904-15). The coding sequences of thepublished HCV replicons were synthesized and subsequently assembled inplasmids using standard molecular biology techniques.

One replicon cell line (“SGR 11-7”) stably expresses HCV replicon RNA,genotype 1b, which consists of (i) the HCV 5′UTR fused to the first 12amino acids of the capsid protein, (ii) the neomycin phosphotransferasegene (neo), and (iii) the IRES from encephalomyocarditis virus (EMCV)and (iv) HCV NS2 to NS5B genes and the HCV 3′UTR. Another replicon cellline (“Huh-1a7”) described by Yi et. al. (Yi et. al. (2004) Journal ofVirology 78(15):7904-15, expressly incorporated by reference in itsentirety) stably expresses HCV replicon RNA, genotype 1a, which consistsof (i) the HCV 5′UTR fused to the first 12 amino acids of the capsidprotein, (ii) the HIV tat protein, (iii) the neomycin phosphotransferasegene (neo), and (iv) the IRES from encephalomyocarditis virus (EMCV) and(vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations(Q1067R, K1691R, S2204I) and the HCV 3′UTR.

These cell lines are maintained at 37° C., 5% CO₂, 100% relativehumidity in DMEM (Cat#11965-084, Invitrogen), with 10% fetal calf serum(“FCS”, Invitrogen), 1% non-essential amino acids (Invitrogen), 1% ofGlutamax (Invitrogen), 1% of 100× penicillin/streptomycin(Cat#15140-122, Invitrogen) and Geneticin (Cat#10131-027, Invitrogen) at0.75 mg/ml or 0.25 mg/ml for 11-7 and Huh-1a7 cells, respectively.

2. HCV Replicon Assay—qRT-PCR.

EC₅₀ values of single agent compounds were determined by HCV RNAdetection using quantitative RT-PCR, according to the manufacturer'sinstructions, with a TAQMAN® One-Step RT-PCR Master Mix Reagents Kit(Cat#AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler.EC₅₀ values of combinations are similarly determined by HCV RNAdetection using quantitative RT-PCR. The TAQMAN primers to use fordetecting and quantifying HCV RNA obtained from Integrated DNATechnologies. HCV RNA is normalized to GAPDH RNA levels in drug-treatedcells, which is detected and quantified using the Human GAPDH EndogenousControl Mix (Applied Biosystems, AB 4310884E). Total cellular RNA ispurified from 96-well plates using the RNAqueous 96 kit (Ambion,Cat#AM1812). Chemical agent cytotoxicity is evaluated using an MTS assayaccording to the manufacturer's directions (Promega).

The compounds of the present invention can be effective against the HCV1a and 1b genotypes. It should also be understood that the compounds ofthe present invention can inhibit multiple genotypes of HCV. In oneembodiment, compounds of the present invention are active against the1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. Table 5 shows the EC₅₀ valuesof representative compounds of the present invention against the HCV 1aand 1b genotypes from the above described qRT-PCR. EC₅₀ ranges againstHCV 1a are as follows: A>1 μM; B 0.1-1 μM; C<0.1 μM.

TABLE 5 Genotype-1a replicon EC₅₀ Example 1a EC₅₀ 1 B

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by Formula I or apharmaceutically acceptable salt, ester, stereoisomer, tautomer,solvate, or combination thereof:

wherein: each D represents a position which is at least 80% deuterated;R₃ is hydrogen, a hydroxy protecting group, —C(O)R₇, —C(O)OR₇, or—C(O)NR_(8a)R_(8b); R₁ is selected from the group consisting of: 1)—C(O)R₇, —C(O)OR₇, and —C(O)NR_(8a)R_(8b); 2) —P(O)(OR_(7a))(OR_(7b));wherein R_(7a)and R_(7b)are each independently selected from the groupconsisting of a) hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl;3) —P(O)(OR_(7a))—O—P(O)(OR_(7b))(OR_(7c)); wherein R_(7a)and R_(7b)arepreviously defined; R_(7c) is selected from the group consisting of a)hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl; 4)—P(O)(OR_(7a))—O—P(O)(OR_(7b))—O—P(O)(OR_(7c))(OR_(7d)); wherein R_(7a),R_(7b) and R_(7c) are previously defined; R_(7d) is selected from thegroup consisting of a) hydrogen; b) unsubstituted or substituted —C₁-C₈alkyl; 5)

 where X is O or S; R₉ is R₇; R₁₀, R₁₁ and R₁₂ are each independentlyselected from the group consisting of hydrogen; and unsubstituted orsubstituted —C₁-C₈ alkyl; or R₁₁ is hydrogen, and R₁₂ and R₁₀ are takentogether with the atoms to which they are attached to form aheterocyclic ring; or R₁₀ is hydrogen or unsubstituted or substituted—C₁-C₈ alkyl and R₁₁ and R₁₂ are taken together with the carbon atom towhich they are attached to form a ring; and R₁₃ is hydrogen or R₇ and 6)

 where X is O or S; n is 1-4; R₁₄ is hydrogen or —(CO)—R₇; Or, R1 and R₃are taken together to form

 where X is O or S; and R₁₅ is selected from the group consisting of a)hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl; c) substitutedor unsubstituted —C₂-C₈ alkenyl; d) substituted or unsubstituted —C₂-C₈alkynyl; e) substituted or unsubstituted aryl; and f) substituted orunsubstituted heteroaryl; R₂a at each occurrence is selected from thegroup consisting of: 1) hydrogen; 2) halogen; 3) Substituted orunsubstituted —C₁-C₈ alkyl; 4) Substituted or unsubstituted —C₂-C₈alkenyl; and 5) Substituted or unsubstituted —C₂-C₈ alkynyl; R_(2b) andR₄ are independently selected from the group consisting of: 1) hydrogen;2) halogen; 3) —CN; 4) —N₃; and 5) OR₉; R₇ at each occurrence isindependently selected from the group consisting of: substituted orunsubstituted —C₁-C₈ alkyl, substituted or unsubstituted —C₂-C₈ alkenyl,substituted or unsubstituted —C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocyclic; R_(8a) and R_(8b) at eachoccurrence are independently selected from the group consisting of:hydrogen and R₇; or alternatively R_(8a) and R_(8b) taken together withthe nitrogen atom to which they are attached form a heterocyclic ring;R₉ at each occurrence is selected from the group consisting of:hydrogen, hydroxy protecting group, R_(10a) , —C(O)R_(10a),—C(O)OR_(10a), and —C(O)NR_(11a)R_(11b); wherein R_(10a) at eachoccurrence is independently selected from the group consisting of:substituted or unsubstituted —C₁-C₈ alkyl, substituted or unsubstituted—C₂-C₈ alkenyl, substituted or unsubstituted —C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocyclic; R_(11a) and R_(11b) at eachoccurrence are each independently selected from the group consisting of:hydrogen and R_(10a); or alternatively R_(11a) and R_(11b) takentogether with the nitrogen atom to which they are attached form aheterocyclic ring; R_(5a) and R_(5b) are independently selected from thegroup consisting of: 1) hydrogen; 2) substituted or unsubstituted —C₁-C₈alkyl; 3) substituted or unsubstituted —C₂-C₈ alkenyl; and 4)substituted or unsubstituted —C₂-C₈ alkynyl; or R₅a and R₅b are takentogether with the carbon atom to which they are attached to form a groupselected from —C₃-C₈ cycloalkyl, —C₃-C₈ cycloalkenyl, or —C₃-C₈cycloalkynyl.
 2. A compound of claim 1 represented by Formula III or apharmaceutically acceptable salt, ester, stereoisomer, tautomer,solvate, or combination thereof:

wherein R_(2a), R_(2b), R₄, R_(5a), R_(5b), and R₇ are as previouslydefined.
 3. A compound of claim 1 represented by Formula IV or apharmaceutically acceptable salt, ester, stereoisomer, tautomer,solvate, or combination thereof:

wherein X, R_(2a), R_(2b), R₃, R₄, R_(5a), R_(5b), R₉, R₁₀, R₁₁, R₁₂,and R₁₃ are as previously defined.
 4. A compound of claim 1 representedby Formula V or a pharmaceutically acceptable salt, ester, stereoisomer,tautomer, solvate, or combination thereof:

wherein n, X, R_(2a), R_(2b), R₃, R₄, R_(5a), R_(5b), R_(8a), R_(8b),and R₁₄ are as previously defined.
 5. A compound of claim 1 representedby Formula VI or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof:

wherein X, R_(2a), R_(2b), R_(5a), R_(5b), and R₁₅ are as previouslydefined.
 6. A compound selected from (a) compounds represented byFormula VII wherein, R_(2a), R_(2b), R₉, R₁₁, R₁₂, and R₁₃ aredelineated for each compound in Table 1:

TABLE 1 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃  1 Me OH Ph Me H iPr  2 MeOH Ph Me H Me  3 Me OH Ph Me H Et  4 Me OH Ph Me H Bn  5 Me OH Ph Me HCH₂CH(CH₃)₂  6 Me F Ph Me H iPr  7 Me F Ph Me H Me  8 Me F Ph Me H Et  9Me F Ph Me H Bn  10 Me F Ph Me H CH₂CH(CH₃)₂  11 Me OH Ph H H iPr  12 MeOH Ph H H Me  13 Me OH Ph H H Et  14 Me OH Ph H H Bn  15 Me OH Ph H HCH₂CH(CH₃)₂  16 Me F Ph H H iPr  17 Me F Ph H H Me  18 Me F Ph H H Et 19 Me F Ph H H Bn  20 Me F Ph H H CH₂CH(CH₃)₂  21 Me OH Ph iPr H iPr 22 Me OH Ph iPr H Me  23 Me OH Ph iPr H Et  24 Me OH Ph iPr H Bn  25 MeOH Ph iPr H CH₂CH(CH₃)₂  26 Me F Ph iPr H iPr  27 Me F Ph iPr H Me  28Me F Ph iPr H Et  29 Me F Ph iPr H Bn  30 Me F Ph iPr H CH₂CH(CH₃)₂  31Me OH Ph CH₂CH(CH₃)₂ H iPr  32 Me OH Ph CH₂CH(CH₃)₂ H Me  33 Me OH PhCH₂CH(CH₃)₂ H Et  34 Me OH Ph CH₂CH(CH₃)₂ H Bn  35 Me OH Ph CH₂CH(CH₃)₂H CH₂CH(CH₃)₂  36 Me F Ph CH₂CH(CH₃)₂ H iPr  37 Me F Ph CH₂CH(CH₃)₂ H Me 38 Me F Ph CH₂CH(CH₃)₂ H Et  39 Me F Ph CH₂CH(CH₃)₂ H Bn  40 Me F PhCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂  41 Me OH Ph CH₂Ph H iPr  42 Me OH Ph CH₂Ph HMe  43 Me OH Ph CH₂Ph H Et  44 Me OH Ph CH₂Ph H Bn  45 Me OH Ph CH₂Ph HCH₂CH(CH₃)₂  46 Me F Ph CH₂Ph H iPr  47 Me F Ph CH₂Ph H Me  48 Me F PhCH₂Ph H Et  49 Me F Ph CH₂Ph H Bn  50 Me F Ph CH₂Ph H CH₂CH(CH₃)₂  51 MeOH 1-Naphthyl Me H iPr  52 Me OH 1-Naphthyl Me H Me  53 Me OH 1-NaphthylMe H Et  54 Me OH 1-Naphthyl Me H Bn  55 Me OH 1-Naphthyl Me HCH₂CH(CH₃)₂  56 Me F 1-Naphthyl Me H iPr  57 Me F 1-Naphthyl Me H Me  58Me F 1-Naphthyl Me H Et  59 Me F 1-Naphthyl Me H Bn  60 Me F 1-NaphthylMe H CH₂CH(CH₃)₂  61 Me OH 1-Naphthyl H H iPr  62 Me OH 1-Naphthyl H HMe  63 Me OH 1-Naphthyl H H Et  64 Me OH 1-Naphthyl H H Bn  65 Me OH1-Naphthyl H H CH₂CH(CH₃)₂  66 Me F 1-Naphthyl H H iPr  67 Me F1-Naphthyl H H Me  68 Me F 1-Naphthyl H H Et  69 Me F 1-Naphthyl H H Bn 70 Me F 1-Naphthyl H H CH₂CH(CH₃)₂  71 Me OH 1-Naphthyl iPr H iPr  72Me OH 1-Naphthyl iPr H Me  73 Me OH 1-Naphthyl iPr H Et  74 Me OH1-Naphthyl iPr H Bn  75 Me OH 1-Naphthyl iPr H CH₂CH(CH₃)₂  76 Me F1-Naphthyl iPr H iPr  77 Me F 1-Naphthyl iPr H Me  78 Me F 1-NaphthyliPr H Et  79 Me F 1-Naphthyl iPr H Bn  80 Me F 1-Naphthyl iPr HCH₂CH(CH₃)₂  81 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H iPr  82 Me OH 1-NaphthylCH₂CH(CH₃)₂ H Me  83 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Et  84 Me OH1-Naphthyl CH₂CH(CH₃)₂ H Bn  85 Me OH 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂  86 Me F 1-Naphthyl CH₂CH(CH₃)₂ H iPr  87 Me F 1-NaphthylCH₂CH(CH₃)₂ H Me  88 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Et  89 Me F1-Naphthyl CH₂CH(CH₃)₂ H Bn  90 Me F 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂  91 Me OH 1-Naphthyl CH₂Ph H iPr  92 Me OH 1-Naphthyl CH₂PhH Me  93 Me OH 1-Naphthyl CH₂Ph H Et  94 Me OH 1-Naphthyl CH₂Ph H Bn  95Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂  96 Me F 1-Naphthyl CH₂Ph H iPr  97Me F 1-Naphthyl CH₂Ph H Me  98 Me F 1-Naphthyl CH₂Ph H Et  99 Me F1-Naphthyl CH₂Ph H Bn 100 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 101 Me OHp-F-Phenyl Me H iPr 102 Me OH p-F-Phenyl Me H Me 103 Me OH p-F-Phenyl MeH Et 104 Me OH p-F-Phenyl Me H Bn 105 Me OH p-F-Phenyl Me H CH₂CH(CH₃)₂106 Me F p-F-Phenyl Me H iPr 107 Me F p-F-Phenyl Me H Me 108 Me Fp-F-Phenyl Me H Et 109 Me F p-F-Phenyl Me H Bn 110 Me F p-F-Phenyl Me HCH₂CH(CH₃)₂ 111 Me OH p-F-Phenyl H H iPr 112 Me OH p-F-Phenyl H H Me 113Me OH p-F-Phenyl H H Et 114 Me OH p-F-Phenyl H H Bn 115 Me OH p-F-PhenylH H CH₂CH(CH₃)₂ 116 Me F p-F-Phenyl H H iPr 117 Me F p-F-Phenyl H H Me118 Me F p-F-Phenyl H H Et 119 Me F p-F-Phenyl H H Bn 120 Me Fp-F-Phenyl H H CH₂CH(CH₃)₂ 121 Me OH p-F-Phenyl iPr H iPr 122 Me OHp-F-Phenyl iPr H Me 123 Me OH p-F-Phenyl iPr H Et 124 Me OH p-F-PhenyliPr H Bn 125 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 126 Me F p-F-Phenyl iPrH iPr 127 Me F p-F-Phenyl iPr H Me 128 Me F p-F-Phenyl iPr H Et 129 Me Fp-F-Phenyl iPr H Bn 130 Me F p-F-Phenyl iPr H CH₂CH(CH₃)₂ 131 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H iPr 132 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Me 133Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 134 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Bn135 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 136 Me F p-F-PhenylCH₂CH(CH₃)₂ H iPr 137 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Me 138 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Et 139 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Bn 140 MeF p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 141 Me OH p-F-Phenyl CH₂Ph H iPr142 Me OH p-F-Phenyl CH₂Ph H Me 143 Me OH p-F-Phenyl CH₂Ph H Et 144 MeOH p-F-Phenyl CH₂Ph H Bn 145 Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 146 MeF p-F-Phenyl CH₂Ph H iPr 147 Me F p-F-Phenyl CH₂Ph H Me 148 Me Fp-F-Phenyl CH₂Ph H Et 149 Me F p-F-Phenyl CH₂Ph H Bn 150 Me F p-F-PhenylCH₂Ph H CH₂CH(CH₃)₂ 151 Me OH iPr Me H iPr 152 Me OH iPr Me H Me 153 MeOH iPr Me H Et 154 Me OH iPr Me H Bn 155 Me OH iPr Me H CH₂CH(CH₃)₂ 156Me F iPr Me H iPr 157 Me F iPr Me H Me 158 Me F iPr Me H Et 159 Me F iPrMe H Bn 160 Me F iPr Me H CH₂CH(CH₃)₂ 161 Me OH iPr H H iPr 162 Me OHiPr H H Me 163 Me OH iPr H H Et 164 Me OH iPr H H Bn 165 Me OH iPr H HCH₂CH(CH₃)₂ 166 Me F iPr H H iPr 167 Me F iPr H H Me 168 Me F iPr H H Et169 Me F iPr H H Bn 170 Me F iPr H H CH₂CH(CH₃)₂ 171 Me OH iPr iPr H iPr172 Me OH iPr iPr H Me 173 Me OH iPr iPr H Et 174 Me OH iPr iPr H Bn 175Me OH iPr iPr H CH₂CH(CH₃)₂ 176 Me F iPr iPr H iPr 177 Me F iPr iPr H Me178 Me F iPr iPr H Et 179 Me F iPr iPr H Bn 180 Me F iPr iPr HCH₂CH(CH₃)₂ 181 Me OH iPr CH₂CH(CH₃)₂ H iPr 182 Me OH iPr CH₂CH(CH₃)₂ HMe 183 Me OH iPr CH₂CH(CH₃)₂ H Et 184 Me OH iPr CH₂CH(CH₃)₂ H Bn 185 MeOH iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 186 Me F iPr CH₂CH(CH₃)₂ H iPr 187 Me FiPr CH₂CH(CH₃)₂ H Me 188 Me F iPr CH₂CH(CH₃)₂ H Et 189 Me F iPrCH₂CH(CH₃)₂ H Bn 190 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 191 Me OH iPrCH₂Ph H iPr 192 Me OH iPr CH₂Ph H Me 193 Me OH iPr CH₂Ph H Et 194 Me OHiPr CH₂Ph H Bn 195 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 196 Me F iPr CH₂Ph HiPr 197 Me F iPr CH₂Ph H Me 198 Me F iPr CH₂Ph H Et 199 Me F iPr CH₂Ph HBn 200 Me F iPr CH₂Ph H CH₂CH(CH₃)₂

(b) compounds represented by Formula VIII, wherein, R_(2a), R_(2b), R₉,R₁₁, R₁₂, and R₁₃ are delineated for each compound in Table 2:

TABLE 2 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃ 201 Me OH Ph Me H iPr 202Me OH Ph Me H Me 203 Me OH Ph Me H Et 204 Me OH Ph Me H Bn 205 Me OH PhMe H CH₂CH(CH₃)₂ 206 Me F Ph Me H iPr 207 Me F Ph Me H Me 208 Me F Ph MeH Et 209 Me F Ph Me H Bn 210 Me F Ph Me H CH₂CH(CH₃)₂ 211 Me OH Ph H HiPr 212 Me OH Ph H H Me 213 Me OH Ph H H Et 214 Me OH Ph H H Bn 215 MeOH Ph H H CH₂CH(CH₃)₂ 216 Me F Ph H H iPr 217 Me F Ph H H Me 218 Me F PhH H Et 219 Me F Ph H H Bn 220 Me F Ph H H CH₂CH(CH₃)₂ 221 Me OH Ph iPr HiPr 222 Me OH Ph iPr H Me 223 Me OH Ph iPr H Et 224 Me OH Ph iPr H Bn225 Me OH Ph iPr H CH₂CH(CH₃)₂ 226 Me F Ph iPr H iPr 227 Me F Ph iPr HMe 228 Me F Ph iPr H Et 229 Me F Ph iPr H Bn 230 Me F Ph iPr HCH₂CH(CH₃)₂ 231 Me OH Ph CH₂CH(CH₃)₂ H iPr 232 Me OH Ph CH₂CH(CH₃)₂ H Me233 Me OH Ph CH₂CH(CH₃)₂ H Et 234 Me OH Ph CH₂CH(CH₃)₂ H Bn 235 Me OH PhCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 236 Me F Ph CH₂CH(CH₃)₂ H iPr 237 Me F PhCH₂CH(CH₃)₂ H Me 238 Me F Ph CH₂CH(CH₃)₂ H Et 239 Me F Ph CH₂CH(CH₃)₂ HBn 240 Me F Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 241 Me OH Ph CH₂Ph H iPr 242 MeOH Ph CH₂Ph H Me 243 Me OH Ph CH₂Ph H Et 244 Me OH Ph CH₂Ph H Bn 245 MeOH Ph CH₂Ph H CH₂CH(CH₃)₂ 246 Me F Ph CH₂Ph H iPr 247 Me F Ph CH₂Ph H Me248 Me F Ph CH₂Ph H Et 249 Me F Ph CH₂Ph H Bn 250 Me F Ph CH₂Ph HCH₂CH(CH₃)₂ 251 Me OH 1-Naphthyl Me H iPr 252 Me OH 1-Naphthyl Me H Me253 Me OH 1-Naphthyl Me H Et 254 Me OH 1-Naphthyl Me H Bn 255 Me OH1-Naphthyl Me H CH₂CH(CH₃)₂ 256 Me F 1-Naphthyl Me H iPr 257 Me F1-Naphthyl Me H Me 258 Me F 1-Naphthyl Me H Et 259 Me F 1-Naphthyl Me HBn 260 Me F 1-Naphthyl Me H CH₂CH(CH₃)₂ 261 Me OH 1-Naphthyl H H iPr 262Me OH 1-Naphthyl H H Me 263 Me OH 1-Naphthyl H H Et 264 Me OH 1-NaphthylH H Bn 265 Me OH 1-Naphthyl H H CH₂CH(CH₃)₂ 266 Me F 1-Naphthyl H H iPr267 Me F 1-Naphthyl H H Me 268 Me F 1-Naphthyl H H Et 269 Me F1-Naphthyl H H Bn 270 Me F 1-Naphthyl H H CH₂CH(CH₃)₂ 271 Me OH1-Naphthyl iPr H iPr 272 Me OH 1-Naphthyl iPr H Me 273 Me OH 1-NaphthyliPr H Et 274 Me OH 1-Naphthyl iPr H Bn 275 Me OH 1-Naphthyl iPr HCH₂CH(CH₃)₂ 276 Me F 1-Naphthyl iPr H iPr 277 Me F 1-Naphthyl iPr H Me278 Me F 1-Naphthyl iPr H Et 279 Me F 1-Naphthyl iPr H Bn 280 Me F1-Naphthyl iPr H CH₂CH(CH₃)₂ 281 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H iPr 282Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Me 283 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Et284 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Bn 285 Me OH 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 286 Me F 1-Naphthyl CH₂CH(CH₃)₂ H iPr 287 Me F 1-NaphthylCH₂CH(CH₃)₂ H Me 288 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Et 289 Me F1-Naphthyl CH₂CH(CH₃)₂ H Bn 290 Me F 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 291 Me OH 1-Naphthyl CH₂Ph H iPr 292 Me OH 1-Naphthyl CH₂PhH Me 293 Me OH 1-Naphthyl CH₂Ph H Et 294 Me OH 1-Naphthyl CH₂Ph H Bn 295Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 296 Me F 1-Naphthyl CH₂Ph H iPr 297Me F 1-Naphthyl CH₂Ph H Me 298 Me F 1-Naphthyl CH₂Ph H Et 299 Me F1-Naphthyl CH₂Ph H Bn 300 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 301 Me OHp-F-Phenyl Me H iPr 302 Me OH p-F-Phenyl Me H Me 303 Me OH p-F-Phenyl MeH Et 304 Me OH p-F-Phenyl Me H Bn 305 Me OH p-F-Phenyl Me H CH₂CH(CH₃)₂306 Me F p-F-Phenyl Me H iPr 307 Me F p-F-Phenyl Me H Me 308 Me Fp-F-Phenyl Me H Et 309 Me F p-F-Phenyl Me H Bn 310 Me F p-F-Phenyl Me HCH₂CH(CH₃)₂ 311 Me OH p-F-Phenyl H H iPr 312 Me OH p-F-Phenyl H H Me 313Me OH p-F-Phenyl H H Et 314 Me OH p-F-Phenyl H H Bn 315 Me OH p-F-PhenylH H CH₂CH(CH₃)₂ 316 Me F p-F-Phenyl H H iPr 317 Me F p-F-Phenyl H H Me318 Me F p-F-Phenyl H H Et 319 Me F p-F-Phenyl H H Bn 320 Me Fp-F-Phenyl H H CH₂CH(CH₃)₂ 321 Me OH p-F-Phenyl iPr H iPr 322 Me OHp-F-Phenyl iPr H Me 323 Me OH p-F-Phenyl iPr H Et 324 Me OH p-F-PhenyliPr H Bn 325 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 326 Me F p-F-Phenyl iPrH iPr 327 Me F p-F-Phenyl iPr H Me 328 Me F p-F-Phenyl iPr H Et 329 Me Fp-F-Phenyl iPr H Bn 330 Me F p-F-Phenyl iPr H CH₂CH(CH₃)₂ 331 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H iPr 332 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Me 333Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 334 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Bn335 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 336 Me F p-F-PhenylCH₂CH(CH₃)₂ H iPr 337 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Me 338 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Et 339 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Bn 340 MeF p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 341 Me OH p-F-Phenyl CH₂Ph H iPr342 Me OH p-F-Phenyl CH₂Ph H Me 343 Me OH p-F-Phenyl CH₂Ph H Et 344 MeOH p-F-Phenyl CH₂Ph H Bn 345 Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 346 MeF p-F-Phenyl CH₂Ph H iPr 347 Me F p-F-Phenyl CH₂Ph H Me 348 Me Fp-F-Phenyl CH₂Ph H Et 349 Me F p-F-Phenyl CH₂Ph H Bn 350 Me F p-F-PhenylCH₂Ph H CH₂CH(CH₃)₂ 351 Me OH iPr Me H iPr 352 Me OH iPr Me H Me 353 MeOH iPr Me H Et 354 Me OH iPr Me H Bn 355 Me OH iPr Me H CH₂CH(CH₃)₂ 356Me F iPr Me H iPr 357 Me F iPr Me H Me 358 Me F iPr Me H Et 359 Me F iPrMe H Bn 360 Me F iPr Me H CH₂CH(CH₃)₂ 361 Me OH iPr H H iPr 362 Me OHiPr H H Me 363 Me OH iPr H H Et 364 Me OH iPr H H Bn 365 Me OH iPr H HCH₂CH(CH₃)₂ 366 Me F iPr H H iPr 367 Me F iPr H H Me 368 Me F iPr H H Et369 Me F iPr H H Bn 370 Me F iPr H H CH₂CH(CH₃)₂ 371 Me OH iPr iPr H iPr372 Me OH iPr iPr H Me 373 Me OH iPr iPr H Et 374 Me OH iPr iPr H Bn 375Me OH iPr iPr H CH₂CH(CH₃)₂ 376 Me F iPr iPr H iPr 377 Me F iPr iPr H Me378 Me F iPr iPr H Et 379 Me F iPr iPr H Bn 380 Me F iPr iPr HCH₂CH(CH₃)₂ 381 Me OH iPr CH₂CH(CH₃)₂ H iPr 382 Me OH iPr CH₂CH(CH₃)₂ HMe 383 Me OH iPr CH₂CH(CH₃)₂ H Et 384 Me OH iPr CH₂CH(CH₃)₂ H Bn 385 MeOH iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 386 Me F iPr CH₂CH(CH₃)₂ H iPr 387 Me FiPr CH₂CH(CH₃)₂ H Me 388 Me F iPr CH₂CH(CH₃)₂ H Et 389 Me F iPrCH₂CH(CH₃)₂ H Bn 390 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 391 Me OH iPrCH₂Ph H iPr 392 Me OH iPr CH₂Ph H Me 393 Me OH iPr CH₂Ph H Et 194 Me OHiPr CH₂Ph H Bn 395 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 396 Me F iPr CH₂Ph HiPr 397 Me F iPr CH₂Ph H Me 398 Me F iPr CH₂Ph H Et 399 Me F iPr CH₂Ph HBn 400 Me F iPr CH₂Ph H CH₂CH(CH₃)₂

(c) compounds represented by Formula IX, wherein, R_(2a), R_(2b), R₉,R₁₁, R₁₂, and R₁₃ are delineated for each compound in Table 3:

TABLE 3 Example R_(2a) R_(2b) R₉ R₁₁ R₁₂ R₁₃ 401 Me OH Ph Me H iPr 402Me OH Ph Me H Me 403 Me OH Ph Me H Et 404 Me OH Ph Me H Bn 405 Me OH PhMe H CH₂CH(CH₃)₂ 406 Me F Ph Me H iPr 407 Me F Ph Me H Me 408 Me F Ph MeH Et 409 Me F Ph Me H Bn 410 Me F Ph Me H CH₂CH(CH₃)₂ 411 Me OH Ph H HiPr 412 Me OH Ph H H Me 413 Me OH Ph H H Et 414 Me OH Ph H H Bn 415 MeOH Ph H H CH₂CH(CH₃)₂ 416 Me F Ph H H iPr 417 Me F Ph H H Me 418 Me F PhH H Et 419 Me F Ph H H Bn 420 Me F Ph H H CH₂CH(CH₃)₂ 421 Me OH Ph iPr HiPr 422 Me OH Ph iPr H Me 423 Me OH Ph iPr H Et 424 Me OH Ph iPr H Bn425 Me OH Ph iPr H CH₂CH(CH₃)₂ 426 Me F Ph iPr H iPr 427 Me F Ph iPr HMe 428 Me F Ph iPr H Et 429 Me F Ph iPr H Bn 430 Me F Ph iPr HCH₂CH(CH₃)₂ 431 Me OH Ph CH₂CH(CH₃)₂ H iPr 432 Me OH Ph CH₂CH(CH₃)₂ H Me433 Me OH Ph CH₂CH(CH₃)₂ H Et 434 Me OH Ph CH₂CH(CH₃)₂ H Bn 435 Me OH PhCH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 436 Me F Ph CH₂CH(CH₃)₂ H iPr 437 Me F PhCH₂CH(CH₃)₂ H Me 438 Me F Ph CH₂CH(CH₃)₂ H Et 439 Me F Ph CH₂CH(CH₃)₂ HBn 440 Me F Ph CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 441 Me OH Ph CH₂Ph H iPr 442 MeOH Ph CH₂Ph H Me 443 Me OH Ph CH₂Ph H Et 444 Me OH Ph CH₂Ph H Bn 445 MeOH Ph CH₂Ph H CH₂CH(CH₃)₂ 446 Me F Ph CH₂Ph H iPr 447 Me F Ph CH₂Ph H Me448 Me F Ph CH₂Ph H Et 449 Me F Ph CH₂Ph H Bn 450 Me F Ph CH₂Ph HCH₂CH(CH₃)₂ 451 Me OH 1-Naphthyl Me H iPr 452 Me OH 1-Naphthyl Me H Me453 Me OH 1-Naphthyl Me H Et 454 Me OH 1-Naphthyl Me H Bn 455 Me OH1-Naphthyl Me H CH₂CH(CH₃)₂ 456 Me F 1-Naphthyl Me H iPr 457 Me F1-Naphthyl Me H Me 458 Me F 1-Naphthyl Me H Et 459 Me F 1-Naphthyl Me HBn 460 Me F 1-Naphthyl Me H CH₂CH(CH₃)₂ 461 Me OH 1-Naphthyl H H iPr 462Me OH 1-Naphthyl H H Me 463 Me OH 1-Naphthyl H H Et 464 Me OH 1-NaphthylH H Bn 465 Me OH 1-Naphthyl H H CH₂CH(CH₃)₂ 466 Me F 1-Naphthyl H H iPr467 Me F 1-Naphthyl H H Me 468 Me F 1-Naphthyl H H Et 469 Me F1-Naphthyl H H Bn 470 Me F 1-Naphthyl H H CH₂CH(CH₃)₂ 471 Me OH1-Naphthyl iPr H iPr 472 Me OH 1-Naphthyl iPr H Me 473 Me OH 1-NaphthyliPr H Et 474 Me OH 1-Naphthyl iPr H Bn 475 Me OH 1-Naphthyl iPr HCH₂CH(CH₃)₂ 476 Me F 1-Naphthyl iPr H iPr 477 Me F 1-Naphthyl iPr H Me478 Me F 1-Naphthyl iPr H Et 479 Me F 1-Naphthyl iPr H Bn 480 Me F1-Naphthyl iPr H CH₂CH(CH₃)₂ 481 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H iPr 482Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Me 483 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Et484 Me OH 1-Naphthyl CH₂CH(CH₃)₂ H Bn 485 Me OH 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 486 Me F 1-Naphthyl CH₂CH(CH₃)₂ H iPr 487 Me F 1-NaphthylCH₂CH(CH₃)₂ H Me 488 Me F 1-Naphthyl CH₂CH(CH₃)₂ H Et 489 Me F1-Naphthyl CH₂CH(CH₃)₂ H Bn 490 Me F 1-Naphthyl CH₂CH(CH₃)₂ HCH₂CH(CH₃)₂ 491 Me OH 1-Naphthyl CH₂Ph H iPr 492 Me OH 1-Naphthyl CH₂PhH Me 493 Me OH 1-Naphthyl CH₂Ph H Et 494 Me OH 1-Naphthyl CH₂Ph H Bn 495Me OH 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 496 Me F 1-Naphthyl CH₂Ph H iPr 497Me F 1-Naphthyl CH₂Ph H Me 498 Me F 1-Naphthyl CH₂Ph H Et 499 Me F1-Naphthyl CH₂Ph H Bn 500 Me F 1-Naphthyl CH₂Ph H CH₂CH(CH₃)₂ 501 Me OHp-F-Phenyl Me H iPr 502 Me OH p-F-Phenyl Me H Me 503 Me OH p-F-Phenyl MeH Et 504 Me OH p-F-Phenyl Me H Bn 505 Me OH p-F-Phenyl Me H CH₂CH(CH₃)₂506 Me F p-F-Phenyl Me H iPr 507 Me F p-F-Phenyl Me H Me 508 Me Fp-F-Phenyl Me H Et 509 Me F p-F-Phenyl Me H Bn 510 Me F p-F-Phenyl Me HCH₂CH(CH₃)₂ 511 Me OH p-F-Phenyl H H iPr 512 Me OH p-F-Phenyl H H Me 513Me OH p-F-Phenyl H H Et 514 Me OH p-F-Phenyl H H Bn 515 Me OH p-F-PhenylH H CH₂CH(CH₃)₂ 516 Me F p-F-Phenyl H H iPr 517 Me F p-F-Phenyl H H Me518 Me F p-F-Phenyl H H Et 519 Me F p-F-Phenyl H H Bn 520 Me Fp-F-Phenyl H H CH₂CH(CH₃)₂ 521 Me OH p-F-Phenyl iPr H iPr 522 Me OHp-F-Phenyl iPr H Me 523 Me OH p-F-Phenyl iPr H Et 524 Me OH p-F-PhenyliPr H Bn 525 Me OH p-F-Phenyl iPr H CH₂CH(CH₃)₂ 526 Me F p-F-Phenyl iPrH iPr 527 Me F p-F-Phenyl iPr H Me 528 Me F p-F-Phenyl iPr H Et 529 Me Fp-F-Phenyl iPr H Bn 530 Me F p-F-Phenyl iPr H CH₂CH(CH₃)₂ 531 Me OHp-F-Phenyl CH₂CH(CH₃)₂ H iPr 532 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Me 533Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Et 534 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H Bn535 Me OH p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 536 Me F p-F-PhenylCH₂CH(CH₃)₂ H iPr 537 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Me 538 Me Fp-F-Phenyl CH₂CH(CH₃)₂ H Et 539 Me F p-F-Phenyl CH₂CH(CH₃)₂ H Bn 540 MeF p-F-Phenyl CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 541 Me OH p-F-Phenyl CH₂Ph H iPr542 Me OH p-F-Phenyl CH₂Ph H Me 543 Me OH p-F-Phenyl CH₂Ph H Et 544 MeOH p-F-Phenyl CH₂Ph H Bn 545 Me OH p-F-Phenyl CH₂Ph H CH₂CH(CH₃)₂ 546 MeF p-F-Phenyl CH₂Ph H iPr 547 Me F p-F-Phenyl CH₂Ph H Me 548 Me Fp-F-Phenyl CH₂Ph H Et 549 Me F p-F-Phenyl CH₂Ph H Bn 550 Me F p-F-PhenylCH₂Ph H CH₂CH(CH₃)₂ 551 Me OH iPr Me H iPr 552 Me OH iPr Me H Me 553 MeOH iPr Me H Et 554 Me OH iPr Me H Bn 555 Me OH iPr Me H CH₂CH(CH₃)₂ 556Me F iPr Me H iPr 557 Me F iPr Me H Me 558 Me F iPr Me H Et 559 Me F iPrMe H Bn 560 Me F iPr Me H CH₂CH(CH₃)₂ 561 Me OH iPr H H iPr 562 Me OHiPr H H Me 563 Me OH iPr H H Et 564 Me OH iPr H H Bn 565 Me OH iPr H HCH₂CH(CH₃)₂ 566 Me F iPr H H iPr 567 Me F iPr H H Me 568 Me F iPr H H Et569 Me F iPr H H Bn 570 Me F iPr H H CH₂CH(CH₃)₂ 571 Me OH iPr iPr H iPr572 Me OH iPr iPr H Me 573 Me OH iPr iPr H Et 574 Me OH iPr iPr H Bn 575Me OH iPr iPr H CH₂CH(CH₃)₂ 576 Me F iPr iPr H iPr 577 Me F iPr iPr H Me578 Me F iPr iPr H Et 579 Me F iPr iPr H Bn 580 Me F iPr iPr HCH₂CH(CH₃)₂ 581 Me OH iPr CH₂CH(CH₃)₂ H iPr 582 Me OH iPr CH₂CH(CH₃)₂ HMe 583 Me OH iPr CH₂CH(CH₃)₂ H Et 584 Me OH iPr CH₂CH(CH₃)₂ H Bn 585 MeOH iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 586 Me F iPr CH₂CH(CH₃)₂ H iPr 587 Me FiPr CH₂CH(CH₃)₂ H Me 588 Me F iPr CH₂CH(CH₃)₂ H Et 589 Me F iPrCH₂CH(CH₃)₂ H Bn 590 Me F iPr CH₂CH(CH₃)₂ H CH₂CH(CH₃)₂ 591 Me OH iPrCH₂Ph H iPr 592 Me OH iPr CH₂Ph H Me 593 Me OH iPr CH₂Ph H Et 594 Me OHiPr CH₂Ph H Bn 595 Me OH iPr CH₂Ph H CH₂CH(CH₃)₂ 596 Me F iPr CH₂Ph HiPr 597 Me F iPr CH₂Ph H Me 598 Me F iPr CH₂Ph H Et 599 Me F iPr CH₂Ph HBn 600 Me F iPr CH₂Ph H CH₂CH(CH₃)₂

and (d) compounds represented by Formula X, wherein, R_(2a), R_(2b),R_(5a), R_(5b), R_(8a), and R_(8b) are delineated for each compound inTable 4:

TABLE 4         Compound         R_(2a)         R_(2b)  

601 Me OH PhCH₂NH

602 Me OH PhCH₂NH

603 Me OH PhCH₂NH

604 Me OH ^(i)PrNH

605 Me OH ^(i)PrNH

606 Me OH ^(i)PrNH

607 Me OH ^(t)BuNH

608 Me OH ^(t)BuNH

609 Me OH ^(t)BuNH

610 Me OH

611 Me OH

612 Me OH

613 Me OH

614 Me OH

615 Me OH

616 Me OH

617 Me OH

618 Me OH

619 Me OH NHCH₂CO₂Et

620 Me OH NH CH₂CO₂Et

621 Me OH NH CH₂CO₂Et

622 Me OH NH CH₂CO₂ ^(t)Bu

623 Me OH NH CH₂CO₂ ^(t)Bu

624 Me OH NH CH₂CO₂ ^(t)Bu

625 Me OH NH CH₂CO₂H

626 Me OH NH CH₂CO₂H

627 Me OH NH CH₂CO₂H

628 Me OH NH CH₂CH₂NMe₂

629 Me OH NH CH₂CH₂NMe₂

630 Me OH NH CH₂CH₂NMe₂

631 Me F PhCH₂NH

632 Me F PhCH₂NH

633 Me F PhCH₂NH

634 Me F ^(i)PrNH

635 Me F ^(i)PrNH

636 Me F ^(i)PrNH

637 Me F ^(t)BuNH

638 Me F ^(t)BuNH

639 Me F ^(t)BuNH

640 Me F

641 Me F

642 Me F

643 Me F

644 Me F

645 Me F

646 Me F

647 Me F

648 Me F

649 Me F NHCH₂CO₂Et

650 Me F NH CH₂CO₂Et

651 Me F NH CH₂CO₂Et

652 Me F NH CH₂CO₂ ^(t)Bu

653 Me F NH CH₂CO₂ ^(t)Bu

654 Me F NH CH₂CO₂ ^(t)Bu

655 Me F NH CH₂CO₂H

656 Me F NH CH₂CO₂H

657 Me F NH CH₂CO₂H

658 Me F NH CH₂CH₂NMe₂

659 Me F NH CH₂CH₂NMe₂

660 Me F NH CH₂CH₂NMe₂

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein R_(2a) is C₁-C₆-alkyl; CF₃, or F.
 8. The compound of claim 1,wherein R_(2a) is methyl.
 9. The compound of claim 1, wherein: R_(2a) isC₁-C₆-alkyl, CF₃, or F; R_(2b) is hydrogen, halogen, —CN, —N₃ or OH; R₄is hydrogen, halogen or OH; R_(5a) and R_(5b) are independently hydrogenor C₁-C₆-alkyl or R_(5a) and R_(5b), together with the carbon atom towhich they are attached, form a C₃-C₆-cycloalkyl group; R₉ is aryl,substituted aryl or C₁-C₆-alkyl; R₁₁ is hydrogen, C₁-C₆-alkyl oraryl-C₁-C₃-alkyl; R₁₂ is hydrogen; and R₁₃ is hydrogen, C₁-C₆-alkyl oraryl-C₁-C₃-alkyl.
 10. The compound of claim 9, wherein: R_(2a) ismethyl, CF₃ or F; R_(2b) is F or OH; R₄ is hydrogen; one of R_(5a) andR_(5b) is methyl and the other is hydrogen; or R_(5a) and R_(5b) areboth hydrogen; or R_(5a) and R_(5b), together with the carbon atom towhich they are attached, form a cyclopropyl group; R₉ is phenyl,naphthyl, p-fluorophenyl or isopropyl; R₁₁ is hydrogen, methyl,isopropyl, isobutyl or benzyl; R₁₂ is hydrogen; and R₁₃ is hydrogen,methyl, isopropyl, isobutyl or benzyl.
 11. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptablecarrier or excipient.
 12. The pharmaceutical composition of claim 11,further comprising another anti-HCV agent.
 13. The pharmaceuticalcomposition of claim 11, further comprising an agent selected frominterferon, ribavirin, amantadine, another HCV protease inhibitor, anHCV polymerase inhibitor, an HCV helicase inhibitor, or an internalribosome entry site inhibitor.
 14. The pharmaceutical composition ofclaim 11, further comprising pegylated interferon.
 15. A method oftreating a viral infection in a subject, comprising administering to thesubject a therapeutically effective amount of a compound according toclaim
 1. 16. The method according to claim 15, wherein the viralinfection is hepatitis C virus.
 17. The method of claim 16, furthercomprising administering concurrently an additional anti-hepatitis Cvirus agent.
 18. The method of claim 17, wherein said additionalanti-hepatitis C virus agent is selected from the group consisting ofα-interferon, β-interferon, ribavirin, and amantadine.
 19. The method ofclaim 17, wherein said additional anti-hepatitis C virus agent is aninhibitor of hepatitis C virus helicase, polymerase, metalloprotease, orIRES.